Arylsulfonamides and uses related thereto

ABSTRACT

Arylsulfonamide compounds of formula I are described and have therapeutic utility, particularly in the treatment of diabetes, obesity and related conditions and disorders:

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/109,871, which was filed on Apr. 20, 2005, and it claims the benefitunder 35 USC 119(e) of U.S. Application 60/564,376, filed Apr. 20, 2004,incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

This invention is generally directed to novel compounds, compositions,and the use of either in methods for modulating hydroxysteroiddehydrogenases, such as 11β-HSD1, and for treating or preventingdiseases associated with the modulation of hydroxysteroiddehydrogenases, such as diabetes and obesity. The methods comprise theadministration, to a patient in need thereof, of a therapeuticallyeffective amount of an Aryl Sulfonamide Compound. Novel Aryl SulfonamideCompounds or pharmaceutically acceptable salts, solvates, stereoisomers,or prodrugs thereof are presented herein.

Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy andactivation of steroid hormone receptors by converting steroid hormonesinto their inactive metabolites. For a recent review, see Nobel et al.,Eur. J. Biochem. 2001, 268:4113-4125.

There exist numerous classes of HSDs. The 11-beta-hydroxysteroiddehydrogenases (11β-HSDs) catalyze the interconversion of activeglucocorticoids (such as cortisol and corticosterone), and their inertforms (such as cortisone and 11-dehydrocorticosterone). The isoform11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is expressed inliver, adipose tissue, brain, lung and other glucocorticoid tissue andis a potential target for therapy directed at numerous disorders thatmay be ameliorated by reduction of glucocorticoid action, such asdiabetes, obesity and age-related cognitive dysfunction. Seckl, et al.,Endocrinology, 2001, 142:1371-1376.

It is well known that glucocorticoids play a central role in thedevelopment of diabetes and that glucocorticoids enable the effect ofglucagon on the liver. Long et al., J. Exp. Med. 1936, 63: 465-490; andHoussay, Endocrinology 1942, 30: 884-892. In addition, it has been wellsubstantiated that 11β-HSD1 plays an important role in the regulation oflocal glucocorticoid effect and of glucose production in the liver.Jamieson et al., J. Endocrinol. 2000, 165:685-692. In Walker, et al., J.Clin. Endocrinol. Metab. 1995, 80:3155-3159, it was reported that theadministration of the non-specific 11β-HSD1 inhibitor carbenoxoloneresulted in improved hepatic insulin sensitivity in humans.

Furthermore, the hypothesized mechanism of action of HSDs in thetreatment of diabetes has been supported by various experimentsconducted in mice and rats. These studies showed that the mRNA levelsand activities of two key enzymes in hepatic glucose production,phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase(G6Pase) were reduced upon administration of HSD inhibitors. Inaddition, blood glucose levels and hepatic glucose production were shownto be reduced in 11β-HSD1 knockout mice. Additional data gathered usingthis murine knockout model also confirm that inhibition of 11β-HSD1 willnot cause hypoglycemia, since the basal levels of PEPCK and G6Pase areregulated independently of glucocorticoids. Kotelevtsev et al., Proc.Natl. Acad. Sci. USA 1997, 94: 14924-14929.

HSDs are also believed to play a role in obesity. Obesity is animportant factor in Syndrome X as well as type II (non-insulindependent) diabetes, and omental fat appears to be of central importancein the development of both of these disease, as abdominal obesity hasbeen linked with glucose intolerance, hyperinsulinemia,hypertriglyceridemia, and other factors of Syndrome X (e.g., raisedblood pressure, decreased levels of HDL and increased levels of VLDL).Montague et al., Diabetes 2000, 49:883-888, 2000. It has also beenreported that inhibition of the 11β-HSDs in pre-adipocytes (stromalcells) resulted in a decreased rate of differentiation into adipocytes.This is predicted to result in diminished expansion (possibly reduction)of the omental fat depot, which may lead to reduced central obesity.Bujalska et al., Lancet 1997, 349:1210-1213.

Inhibition of 11β-HSD1 in mature adipocytes is expected to attenuatesecretion of the plasminogen activator inhibitor 1 (PAI-1), which is anindependent cardiovascular risk factor, as reported in Halleux et al.,J. Clin. Endocrinol. Metab. 1999, 84:4097-4105. In addition, acorrelation has been shown to exist between glucocorticoid activity andcertain cardiovascular risk factors. This suggests that a reduction ofthe glucocorticoid effects would be beneficial in the treatment orprevention of certain cardiovascular diseases. Walker et al.,Hypertension 1998, 31:891-895; and Fraser et al., Hypertension 1999,33:1364-1368.

HSDs have also been implicated in the process of appetite control andtherefore are believed to play an additional role in weight-relateddisorders. It is known that adrenalectomy attenuates the effect offasting to increase both food intake and hypothalamic neuropeptide Yexpression. This suggests that glucocorticoids play a role in promotingfood intake and that inhibition of 11β-HSD1 in the brain may increasesatiety, thus resulting in a decreased food intake. Woods et al.,Science 1998, 280:1378-1383.

Another possible therapeutic effect associated with modulation of HSDsis that which is related to various pancreatic aliments. It is reportedthat inhibition of 11β-HSD1 in murine pancreatic β-cells results inincreased insulin secretion. Davani et al., J. Biol. Chem. 2000,275:34841-34844. This follows from the discovery that glucocorticoidswere previously found to be responsible for reduced pancreatic insulinrelease in vivo, Billaudel et al., Horm. Metab. Res. 1979, 11:555-560.Thus, it is suggested that inhibition of 11β-HSD1 would yield otherbeneficial effects in the treatment of diabetes other than the predictedeffects on the liver and fat reduction.

11β-HSD1 also regulates glucocorticoid activity in the brain and thuscontributes to neurotoxicity. Rajan et al., Neuroscience 1996, 16:65-70;and Seckl et al., Neuroendocrinol. 2000, 18:49-99. Stress and/orglucocorticoids are known to influence cognitive function (de Quervainet al., Nature 1998, 394:787-790), and unpublished results indicatesignificant memory improvement in rats treated with a non-specific11β-HSD inhibitor. These reports, in addition to the known effects ofglucocorticoids in the brain, suggest that inhibiting HSDs in the brainmay have a positive therapeutic effect against anxiety and relatedconditions. Tronche et al., Nature Genetics 1999, 23:99-103. 11β-HSD1reactivates 11-DHC to corticosterone in hippocampal cells and canpotentiate kinase neurotoxicity, resulting in age-related learningimpairments. Therefore, selective inhibitors of 11β-HSD1 are believed toprotect against hippocampal function decline with age. Yau et al., ProcNatl. Acad. Sci. USA 2001, 98:4716-4721. Thus, it has been hypothesizedthat inhibition of 11β-HSD1 in the human brain would protect againstdeleterious glucocorticoid-mediated effects on neuronal function, suchas cognitive impairment, depression, and increased appetite.

HSDs are believed to play a role in immunomodulation based on thegeneral perception that glucocorticoids suppress the immune system.There is known to be a dynamic interaction between the immune system andthe HPA (hypothalamopituitary-adrenal) axis (Rook, Baillier's Clin.Endocrinol. Metab. 2000, 13: 576-581), and glucocorticoids help balancebetween cell-mediated responses and humoral responses. Increasedglucocorticoid activity, which may be induced by stress, is associatedwith a humoral response and as such, the inhibition of 11β-HSD1 mayresult in shifting the response towards a cell-based reaction. Incertain disease states, such as tuberculosis, leprosy, and psoriasis,the immune reaction is typically biased towards a humoral response whena cell-based response might be more appropriate. Inhibition of 11β-HSD1is being studied for use to direct a cell-based response in theseinstances. Mason, Immunology Today 1991, 12:57-60. It follows then, thatan alternative utility of 11β-HSD1 inhibition would be to bolster atemporal immune response in association with immunization to ensure thata cell based response would be obtained.

Recent reports suggest that the levels of glucocorticoid targetreceptors and of HSDs are connected with the risks of developingglaucoma. Stokes et al., Invest. Opthalmol. 2000, 41:1629-1638. Further,a connection between inhibition of 11β-HSD1 and a lowering of theintraocular pressure was reported. Walker et al., poster P3-698 at theEndocrine society meeting Jun. 12-15, 1999, San Diego. It was shown thatadministration of the nonspecific 11β-HSD1 inhibitor, carbenoxolone,resulted in the reduction of the intraocular pressure by 20% in normalpatients. In the eye, 11β-HSD1 is expressed exclusively in the basalcells of the corneal epithelium, the non-pigmented epithelialium of thecornea (the site of aqueous production), ciliary muscle, and thesphincter and dilator muscles of the iris. In contrast, the distantisoenzyme 11β-hydroxysteroid dehydrogenase type 2 (“11β-HSD2”) is highlyexpressed in the non-pigmented ciliary epithelium and cornealendothelium. No HSDs have been found at the trabecular meshwork, whichis the site of drainage. Therefore, 11β-HSD1 is suggested to have a rolein aqueous production.

Glucocorticoids also play an essential role in skeletal development andfunction but are detrimental to such development and function whenpresent in excess. Glucocorticoid-induced bone loss is partially derivedfrom suppression of osteoblast proliferation and collagen synthesis, asreported in Kim et al., J. Endocrinol. 1999, 162:371 379. It has beenreported that the detrimental effects of glucocorticoids on bone noduleformation can be lessened by administration of carbenoxolone, which is anon-specific 11β-HSD1 inhibitor. Bellows et al., Bone 1998, 23:119-125.Additional reports suggest that 11β-HSD1 may be responsible forproviding increased levels of active glucocorticoid in osteoclasts, andthus in augmenting bone resorption. Cooper et al., Bone 2000,27:375-381. This data suggests that inhibition of 11β-HSD1 may havebeneficial effects against osteoporosis via one or more mechanisms whichmay act in parallel.

It is known that bile acids inhibit 11β-HSD2 and that such inhibitionresults in a shift in the cortisol/cortisone equilibrium in the favor ofcortisol. Quattropani et al., J. Clin. Invest. November 2001,108:1299-305. A reduction in the hepatic activity of 11β-HSD2 istherefore predicted to reverse the cortisol/cortisone equilibrium tofavor cortisone, which could provide therapeutic benefit in diseasessuch as hypertension.

The various isozymes of the 17-beta-hydroxysteroid dehydrogenases(17β-HSDs) bind to androgen receptors or estrogen receptors and catalyzethe interconversion of various sex hormones including estradiol/estroneand testosterone/androstenedione. To date, six isozymes have beenidentified in humans and are expressed in various human tissuesincluding endometrial tissue, breast tissue, colon tissue, and in thetestes. 17-beta-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) isexpressed in human endometrium and its activity has been reported to belinked to cervical cancer. Kitawaki et al., J. Clin. Endocrin. Metab.,2000, 85:1371-3292-3296. 17-beta-Hydroxysteroid dehydrogenase type 3(17β-HSD3) is expressed in the testes and its modulation may be usefulfor the treatment of androgen-related disorders.

Androgens and estrogens are active in their 17β-hydroxy configurations,whereas their 17-keto derivatives do not bind to androgen and estrogenreceptors and are thus inactive. The conversion between the active andinactive forms (estradiol/estrone and testosterone/androstenedione) ofsex hormones is catalyzed by members of the 17β-HSD family. 17β-HSD1catalyzes the formation of estradiol in breast tissue, which isimportant for the growth of malignant breast tumors. Labrie et al., Mol.Cell. Endocrinol. 1991, 78:C113-C118. A similar role has been suggestedfor 17β-HSD4 in colon cancer. English et al., J. Clin. Endocrinol.Metab. 1999, 84:2080-2085. 17β-HSD3 is almost exclusively expressed inthe testes and converts androstenedione into testosterone. Deficiency ofthis enzyme during fetal development leads to malepseudohermaphroditism. Geissler et al., Nat. Genet. 1994, 7:34-39. Both17β-HSD3 and various 3α-HSD isozymes are involved in complex metabolicpathways which lead to androgen shuffles between inactive and activeforms. Penning et al., Biochem. J. 2000, 351:67-77. Thus, modulation ofcertain HSDs can have potentially beneficial effects in the treatment ofandrogen- and estrogen-related disorders.

The 20-alpha-hydroxysteroid dehydrogenases (20α-HSDs) catalyze theinterconversion of progestins (such as between progesterone and20α-hydroxy progesterone). Other substrates for 20α-HSDs include17α-hydroxypregnenolone or 17α-hydroxyprogesterone, leading to 20α-OHsteroids. Several 20α-HSD isoforms have been identified and 20α-HSDs areexpressed in various tissues, including the placenta, ovaries, testesand adrenals. Peltoketo, et al., J. Mol. Endocrinol. 1999, 23:1-11.

The 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs) catalyze theinterconversion of the androgens dihydrotestosterone (DHT) and5α-androstane-3α,17β-diol and the interconversion of the androgens DHEAand androstenedione and therefore play an important role in androgenmetabolism. Ge et al., Biology of Reproduction 1999, 60:855-860.

International Publications Nos. WO 01/90090, WO 01/90091, WO 01/90092,and WO 03/044009 disclose aryl sulfonamides and their use as 11β-HSD1modulators.

Despite the previous research done in the field of HSD inhibition, thereremains a need for novel compounds that are potent inhibitors of thevarious families of HSDs and efficacious for the treatment ofHSD-mediated conditions such as diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders, depression,hypertension, and others.

BRIEF SUMMARY OF THE INVENTION

In brief, the present invention relates to novel compounds, compositionsthereof and methods for modulating the activity of hydroxysteroiddehydrogenases (HSDs), such as 11β-hydroxysteroid dehydrogenases,17β-hydroxysteroid dehydrogenases, 20α-hydroxysteroid dehydrogenases,and 3α-hydroxysteroid dehydrogenases, including all isoforms thereof,including but not limited to 11β-hydroxysteroid dehydrogenase type 1(hereinafter “11β-HSD1”), 11β-hydroxysteroid dehydrogenase type 2(hereinafter “11β-HSD2”), and 17β-hydroxysteroid dehydrogenase type 3(hereinafter “17β-HSD3”). In a preferred embodiment, the components ofthe invention inhibit HSD activity.

The present invention also relates to methods for treating or preventingdiseases or disorders associated with the action of hydroxysteroiddehydrogenases, comprising administering to a patient in need thereof atherapeutically effective amount of an Aryl Sulfonamide Compound or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof. The invention encompasses both selective and non-selectiveinhibitors of hydroxysteroid dehydrogenases.

It should be understood that selective and non-selective inhibitors ofhydroxysteroid dehydrogenases each have benefits in the treatment orprevention of diseases associated with, for example, abnormal glucoselevels or hypothalmic function. The invention also encompasses selectiveinhibitors of HSDs. Two types of selectivity are contemplated, that withrespect to selectivity for HSDs as a class over other types of receptorsor gene targets related to glucose metabolism, or those which areselective for various HSDs or specific isoforms thereof compared toother HSDs or specific isoforms thereof.

In one embodiment, the Aryl Sulfonamide Compounds can act as selectiveor non-selective 11β-HSD inhibitors. The compounds may inhibit theinterconversion of inactive 11-keto steroids with their active hydroxyequivalents. The present invention provides methods by which theconversion of the inactive to the active form may be controlled, and touseful therapeutic effects which may be obtained as a result of suchcontrol. More specifically, but not exclusively, the invention isconcerned with interconversion between cortisone and cortisol in humans.

In another embodiment, the Aryl Sulfonamide Compounds can act as 11β-HSDinhibitors in vivo.

In another embodiment, the Aryl Sulfonamide Compounds of the presentinvention may be orally active.

The Aryl Sulfonamide Compounds are also useful for modulation ofnumerous metabolic functions including, but not limited to, one or moreof: (i) regulation of carbohydrate metabolism, (ii) regulation ofprotein metabolism, (iii) regulation of lipid metabolism, (iv)regulation of normal growth and/or development, (v) influence oncognitive function, (vi) resistance to stress and mineralocorticoidactivity.

The Aryl Sulfonamide Compounds may also be useful for inhibiting hepaticgluconeogenesis, and may also be effective to relieve the effects ofendogenous glucocorticoids in diabetes mellitus, obesity (includingentripetal obesity), neuronal loss and/or the cognitive impairment ofold age. Thus, in a further aspect, the invention provides the use of aninhibitor of HSDs in methods directed to producing one or moretherapeutic effects in a patient to whom the Aryl Sulfonamide Compoundis administered, said therapeutic effects selected from the groupconsisting of inhibition of hepatic gluconeogenesis, an increase ininsulin sensitivity in adipose tissue and muscle, and the prevention ofor reduction in neuronal loss/cognitive impairment due toglucocorticoid-potentiated neurotoxicity or neural dysfunction ordamage.

The invention further provides methods for treating a condition selectedfrom the group consisting of: hepatic insulin resistance, adipose tissueinsulin resistance, muscle insulin resistance, neuronal loss ordysfunction due to glucocorticoid potentiated neurotoxicity, and anycombination of the aforementioned conditions, the methods comprisingadministering to a patient in need thereof a therapeutically effectiveamount of an Aryl Sulfonamide Compound.

The Aryl Sulfonamide Compounds of the invention are compounds havingFormula (I) as well as their pharmaceutically acceptable salts,solvates, stereoisomers, or prodrugs thereof.

In formula (I), R¹ is selected from —OH, (C₁-C₈)alkyl and(C₁-C₈)haloalkyl; R² and R³ are independently selected from halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl; and N^(cyc)is a nitrogen heterocycle having a formula selected from formula (a),formula (b), formula (c) and formula (d):

In formulae (a) through (d), the substituents, subscripts and variablehave the following meanings:

In formula (a), R^(2a), R^(2a′) and R^(5a) are each independentlyselected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR″, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally R^(2a) and R^(2a′) are combinedto form an oxo (═O) or thiono (═S) group when at least one of R^(3a) andR^(4a) is other than H; and wherein when R^(5a) is —C(O)R′, —C(O)OR′ or—OR″ then at least one of R^(2a), R^(2a′), R^(3a) and R^(4a) is otherthan H; R^(3a) and R^(4a) are each independently selected from H,halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—C(O)N(R′)₂, —OR″, —OC(O)R′, —NR′C(O)OR″, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally two adjacent R^(3a), R^(4a) andR^(5a) members are combined to form a benzene or pyridine ring, fused tothe remainder of N^(cyc); and within formula (a), at least one ofR^(2a), R^(2a′), R^(3a), R^(4a) and R^(5a) is other than H.

In formula (b), R^(2b), R^(2b′) and R^(6b) are each independentlyselected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally R^(2b) and R^(2b′) are combinedto form an oxo (═O) or thiono (═S) group when at least one of R^(3b),R^(4b) and R^(5b) is other than H; R^(3b), R^(4b) and R^(5b) are eachindependently selected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,—C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″,—SO₂R″, —SO₂N(R′)₂, —N(R′)₂, and —NR′C(O)R′; and optionally two adjacentR^(3b), R^(4b), R^(5b) and R^(6b) members are combined to form a benzeneor pyridine ring, fused to the remainder of N^(cyc); and within formula(b), at least one of R^(2b), R^(2b′), R^(3b), R^(4b), R^(5b) and R^(6b)is other than H.

In formula (c), X is O or S(O)_(k) wherein k is an integer of from 0 to2; R^(2c), R^(2c′) and R^(6c) are each independently selected from H,halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″,—SO₂N(R′)₂, —N(R′)₂, and —NR′C(O)R′; and optionally R^(2c) and R^(2c′)are combined to form an oxo (═O) or thiono (═S) group when at least oneof R^(3c) and R^(4c) is other than H; R^(3c) and R^(5c) are eachindependently selected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,—C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂,—S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂, and —NR′C(O)R′; and optionally twoadjacent R^(2c), R^(2c′), R^(3c), R^(5c) and R^(6c) members are combinedto form a benzene or pyridine ring, fused to the remainder of N^(cyc);and within formula (c), at least one of R^(2c), R^(2c′), R^(3c), R^(5c)and R^(6c) is other than H.

In formula (d), the subscript m is an integer of from 1 to 6; thesubscript n is 2 or 3; R^(2d) and R^(2d′) are each independentlyselected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂ and —NR′C(O)R′; and optionally R^(2d) and R^(2d′) are combinedto form an oxo (═O) or thiono (═S) group when at least one of R^(d) isother than H; each R^(d) is independently selected from H, halogen, —CN,—NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally two adjacent R^(d) members arecombined to form a benzene or pyridine ring, fused to the remainder ofN^(cyc); and within formula (d), at least one of R^(2d), R^(2d′) andR^(d) is other than H.

For each of formulae (a)-(d), any fused benzene or pyridine ring portionof N^(cyc) is optionally substituted with from one to four membersselected from halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″,—SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′. Additionally, in these formulae,each occurrence of R′ is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, ortwo R′ groups, when attached to the same nitrogen atom, can be combinedwith the nitrogen atom to which they are attached to form a heterocycleor heteroaryl group; and each occurrence of R″ is independently(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl or aryl(C₁-C₆)alkyl.

Additionally, when N^(cyc) is formula (a), and R^(2a) and R^(2a′) areeach H, then R^(5a) is other than phenyl, furyl, thienyl or pyridyl.Still further, the compounds are other than4-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-3,4-dihydro-N,N-dipropyl-2H-1,4-Benzoxazine-6-ethanamineor its salt (Registry No. 144-62-7);N-[[(3R)-4-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-1,1-dioxido-3-thiomorpholinyl]carbonyl]-L-Tyrosine,1,1-dimethylethyl ester, dimethylcarbamate (Registry No. 220544-72-9);andN-[[(3R)-4-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-1,1-dioxido-3-thiomorpholinyl]carbonyl]-L-Tyrosine,dimethylcarbamate (Registry No. 220545-63-1).

In one aspect, the invention provides pharmaceutical compositionscomprising an Aryl Sulfonamide Compounds and a pharmaceuticallyacceptable vehicle, carrier, excipient or diluent.

In another aspect, the invention provides methods for treatinginsulin-dependent diabetes mellitus comprising administering to apatient in need thereof a therapeutically effective amount of an ArylSulfonamide Compound of Formula (I).

In another aspect, the invention provides methods for treatingnon-insulin-dependent diabetes mellitus comprising administering to apatient in need thereof a therapeutically effective amount of an ArylSulfonamide Compound of Formula (I).

In another aspect, the invention provides methods for treating insulinresistance comprising administering to a patient in need thereof atherapeutically effective amount of an Aryl Sulfonamide Compound ofFormula (I).

In another aspect, the invention provides methods for treating obesitycomprising administering to a patient in need thereof a therapeuticallyeffective amount of an Aryl Sulfonamide Compound of Formula (I).

In another aspect, the invention provides methods for modulatingcortisol production comprising administering to a patient in needthereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

In another aspect, the invention provides methods for modulating hepaticglucose production comprising administering to a patient in need thereofa therapeutically effective amount of an Aryl Sulfonamide Compound ofFormula (I).

In another aspect, the invention provides methods for modulatinghypothalamic function comprising administering to a patient in needthereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

In one aspect, the invention provides methods for treating ahydroxysteroid dehydrogenase-mediated condition or disorder comprisingadministering to a patient in need thereof a therapeutically effectiveamount of an Aryl Sulfonamide Compound of Formula (I).

In another aspect, the invention provides method for modulating thefunction of a hydroxysteroid dehydrogenase in a cell comprisingadministering to a patient in need thereof a therapeutically effectiveamount of an Aryl Sulfonamide Compound of Formula (I).

In a further aspect, the invention provides methods for modulating ahydroxysteroid dehydrogenase, comprising administering to a patient inneed thereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

In still another aspect, the invention provides methods for treating an11β-HSD1-mediated condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of an ArylSulfonamide Compound of Formula (I).

In yet another aspect, the invention provides method for modulating thefunction of 11β-HSD1 in a cell comprising administering to a patient inneed thereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

In a further aspect, the invention provides methods for modulating11β-HSD1, comprising administering to a patient in need thereof atherapeutically effective amount of an Aryl Sulfonamide Compound ofFormula (I).

In one aspect, the invention provides methods for treating an11β-HSD2-mediated condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of an ArylSulfonamide Compound of Formula (I).

In another aspect, the invention provides method for modulating thefunction of 11β-HSD2 in a cell comprising administering to a patient inneed thereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

In a further aspect, the invention provides methods for modulating11β-HSD2, comprising administering to a patient in need thereof atherapeutically effective amount of an Aryl Sulfonamide Compound ofFormula (I).

In one aspect, the invention provides methods for treating an17β-HSD3-mediated condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of an ArylSulfonamide Compound of Formula (I).

In another aspect, the invention provides method for modulating thefunction of 17β-HSD3 in a cell comprising administering to a patient inneed thereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

In a further aspect, the invention provides methods for modulating17β-HSD3, comprising administering to a patient in need thereof atherapeutically effective amount of an Aryl Sulfonamide Compound ofFormula (I).

These and other aspects of this invention will be evident upon referenceto the following detailed description. To that end, certain patent andother documents are cited herein to more specifically set forth variousaspects of this invention. Each of these documents are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms have the following meanings:

The term “alkyl” as used herein refers to a straight or branched chain,saturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C₁-C₆)alkyl is meant to include, but is not limited to methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group canbe unsubstituted or optionally substituted with one or more substituentsas described herein below.

The term “alkenyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one double bond. Examples of a (C₂-C₈)alkenyl group include,but are not limited to, ethylene, propylene, 1-butylene, 2-butylene,isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene,2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene,isoheptene, 1-octene, 2-octene, 3-octene, 4-octene, and isooctene. Analkenyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein below.

The term “alkynyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one triple bond. Examples of a (C₂-C₈)alkynyl group include,but are not limited to, acetylene, propyne, 1-butyne, 2-butyne,1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne,2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. Analkynyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein below.

The term “alkylene” refers to a divalent alkyl group (e.g., an alkylgroup attached to two other moieties, typically as a linking group).Examples of a (C₁-C₇)alkylene include —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, and—CH₂CH₂CH₂CH₂CH₂CH₂CH₂—, as well as branched versions thereof. Analkylene group can be unsubstituted or optionally substituted with oneor more substituents as described herein below.

The term “alkoxy” as used herein refers to an —O-alkyl group having theindicated number of carbon atoms. For example, a (C₁-C₆)alkoxy groupincludes —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,—O-sec-butyl, —O-tert-butyl, —O-pentyl, —O-isopentyl, —O-neopentyl,—O-hexyl, —O-isohexyl, and —O-neohexyl.

The term “aminoalkyl,” as used herein, refers to an alkyl group(typically one to six carbon atoms) wherein from one or more of theC₁-C₆ alkyl group's hydrogen atoms is replaced with an amine of formula—N(R^(a))₂, wherein each occurrence of R^(a) is independently —H or(C₁-C₆)alkyl. Examples of aminoalkyl groups include, but are not limitedto, —CH₂NH₂, —CH₂CH₂NH₂—, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂N(CH₃)₂,t-butylaminomethyl, isopropylaminomethyl and the like.

The term “aryl” as used herein refers to a 6- to 14-membered monocyclic,bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of anaryl group include phenyl and naphthyl. An aryl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein below.

The term “cycloalkyl” as used herein refers to a 3- to 14-memberedsaturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclichydrocarbon ring system. Included in this class are cycloalkyl groupswhich are fused to a benzene ring. Representative cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctyl,cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl,-1,3,5-cyclooctatrienyl, decahydronaphthalene, octahydronaphthalene,hexahydronaphthalene, octahydroindene, hexahydroindene, tetrahydroinden,decahydrobenzocycloheptene, octahydrobenzocycloheptene,hexahydrobenzocycloheptene, tetrahydrobenzocyclopheptene,dodecahydroheptalene, decahydroheptalene, octahydroheptalene,hexahydroheptalene, and tetrahydroheptalene. A cycloalkyl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein below.

The term “halo” as used herein refers to —F, —Cl, —Br or —I.

The term “haloalkyl,” as used herein, refers to a C₁-C₆ alkyl groupwherein from one or more of the C₁-C₆ alkyl group's hydrogen atom isreplaced with a halogen atom, which can be the same or different.Examples of haloalkyl groups include, but are not limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,pentachloroethyl, and 1,1,1-trifluoro-2-bromo-2-chloroethyl.

The term “heteroaryl” as used herein refers to an aromatic heterocyclering of 5 to 14 members and having at least one heteroatom selected fromnitrogen, oxygen and sulfur, and containing at least 1 carbon atom,including monocyclic, bicyclic, and tricyclic ring systems.Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl,pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl,phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl,morpholinyl, dioxanyl, thietanyl and oxazolyl. A heteroaryl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein below.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

As used herein, the term “heterocycle” or “heterocycloalkyl” as usedherein refers to 5- to 14-membered ring systems which are eithersaturated, unsaturated, or aromatic, and which contains from 1 to 4heteroatoms independently selected from nitrogen, oxygen and sulfur, andwherein the nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen heteroatom may be optionally quaternized, including,including monocyclic, bicyclic, and tricyclic ring systems. The bicyclicand tricyclic ring systems may encompass a heterocycle or heteroarylfused to a benzene ring. The heterocycle may be attached via anyheteroatom or carbon atom. Heterocycles include heteroaryls as definedabove. Representative examples of heterocycles include, but are notlimited to, aziridinyl, oxiranyl, thioranyl, triazolyl, tetrazolyl,azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl,azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl,morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl,tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl,furazanyl, pyridinyl, oxazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl,benzthiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl,benzimidazolyl, isoindolyl, indazolyl, benzodiazolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, purinyl, indolyl, isoquinolinyl,quinolinyl, and quinazolinyl. A heterocycle group can be unsubstitutedor optionally substituted with one or more substituents as describedherein below.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group havingthe indicated number of carbon atoms wherein one or more of the alkylgroup's hydrogen atoms is replaced with an —OH group. Examples ofhydroxyalkyl groups include, but are not limited to, —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH,—CH₂CH₂CH₂CH₂CH₂CH₂OH, and branched versions thereof.

Substituents for the alkyl radicals (as well as those groups referred toas alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,cycloalkenyl and heterocycloalkenyl) can be a variety of groups selectedfrom: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halo, —SiR′R″R′″, —OC(O)R′,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″,—NR′″SO₂NR′R″, —NR″CO₂R′, —NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —CN and —NO₂, in a number rangingfrom zero to three, with those groups having zero, one or twosubstituents being particularly preferred. R′, R″ and R′″ eachindependently refer to hydrogen, unsubstituted (C₁-C₈)alkyl,unsubstituted hetero(C₁-C₈)alkyl, unsubstituted aryl and arylsubstituted with one to three substituents selected from -halo,unsubstituted alkyl, unsubstituted alkoxy, unsubstituted thioalkoxy andunsubstituted aryl(C₁-C₄)alkyl. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 5-,6- or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkylgroup will have from zero to three substituents, with those groupshaving two or fewer substituents being preferred in the presentinvention. More preferably, an alkyl or heteroalkyl radical will beunsubstituted or monosubstituted. Most preferably, an alkyl orheteroalkyl radical will be unsubstituted. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups such as trihaloalkyl (e.g., —CF₃ and—CH₂CF₃).

Preferred substituents for the alkyl and heteroalkyl radicals areselected from: —OR′, ═O, —NR′R″, —SR′, -halo, —SiR′R″R′″, —OC(O)R′,—C(O)R′, —CO₂R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′,—NR′″SO₂NR′R″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —CN and —NO₂,where R′, R″ and R′″ are as defined above. Further preferredsubstituents are selected from: —OR′, ═O, —NR′R″, -halo, —OC(O)R′,—CO₂R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′″SO₂NR′R″,—SO₂R′, —SO₂NR′R″, —NR″SO₂R′—CN and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand selected from: -halo, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂,—CO₂R′, —C(O)NR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′,—NR′″C(O)NR′R″, —NR′″SO₂NR′R″, —NHC(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —N₃, —CH(Ph)₂,perfluoroalkoxy and perfluoro(C₁-C₄)alkyl, in a number ranging from zeroto the total number of open valences on the aromatic ring system; andwhere R′, R″ and R′″ are independently selected from hydrogen,unsubstituted (C₁-C₈)alkyl, unsubstituted hetero(C₁-C₈)alkyl,unsubstituted aryl, unsubstituted heteroaryl, unsubstitutedaryl(C₁-C₄)alkyl and unsubstituted aryloxy(C₁-C₄)alkyl. Typically, anaryl or heteroaryl group will have from zero to three substituents, withthose groups having two or fewer substituents being preferred in thepresent invention. In one embodiment of the invention, an aryl orheteroaryl group will be unsubstituted or monosubstituted. In anotherembodiment, an aryl or heteroaryl group will be unsubstituted.

Preferred substituents for aryl and heteroaryl groups are selected from:-halo, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′,—N₃, —CH(Ph)₂, perfluoroalkoxy and perfluoro(C₁-C₄)alkyl, where R′ andR″ are as defined above. Further preferred substituents are selectedfrom: -halo, —OR′, —OC(O)R′, —NR′R″, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—NR″C(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, perfluoroalkoxy andperfluoro(C₁-C₄)alkyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted (C₁-C₆)alkyl.

It is to be understood that the substituent —CO₂H, as used herein, maybe optionally replaced with bioisosteric replacements such as:

and the like. See, e.g., The Practice of Medicinal Chemistry; Wermuth,C. G., Ed.; Academic Press: New York, 1996; p. 203.

The Aryl Sulfonamide Compound can also exist in various isomeric forms,including configurational, geometric and conformational isomers, as wellas existing in various tautomeric forms, particularly those that differin the point of attachment of a hydrogen atom. As used herein, the term“isomer” is intended to encompass all isomeric forms of an ArylSulfonamide Compound, including tautomeric forms of the compound.

Certain Aryl Sulfonamide Compounds may have asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. AnAryl Sulfonamide Compound can be in the form of an optical isomer or adiastereomer. Accordingly, the invention encompasses Aryl SulfonamideCompounds and their uses as described herein in the form of theiroptical isomers, diasteriomers and mixtures thereof, including a racemicmixture. Optical isomers of the Aryl Sulfonamide Compounds can beobtained by known techniques such as asymmetric synthesis, chiralchromatography, simulated moving bed technology or via chemicalseparation of stereoisomers through the employment of optically activeresolving agents.

As used herein and unless otherwise indicated, the term “stereoisomer”or means one stereoisomer of a compound that is substantially free ofother stereoisomers of that compound. For example, a stereomericallypure compound having one chiral center will be substantially free of theopposite enantiomer of the compound. A stereomerically pure compoundhaving two chiral centers will be substantially free of otherdiastereomers of the compound. A typical stereomerically pure compoundcomprises greater than about 80% by weight of one stereoisomer of thecompound and less than about 20% by weight of other stereoisomers of thecompound, more preferably greater than about 90% by weight of onestereoisomer of the compound and less than about 10% by weight of theother stereoisomers of the compound, even more preferably greater thanabout 95% by weight of one stereoisomer of the compound and less thanabout 5% by weight of the other stereoisomers of the compound, and mostpreferably greater than about 97% by weight of one stereoisomer of thecompound and less than about 3% by weight of the other stereoisomers ofthe compound.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structurecontrols. In addition, if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of it.

An Aryl Sulfonamide Compound can be in the form of a pharmaceuticallyacceptable salt. Depending on the it's structure, the phrase“pharmaceutically acceptable salt,” as used herein, refers to apharmaceutically acceptable organic or inorganic acid or base salt of anAryl Sulfonamide Compound. Representative pharmaceutically acceptablesalts include, e.g., alkali metal salts, alkali earth salts, ammoniumsalts, water-soluble and water-insoluble salts, such as the acetate,amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate,esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.Furthermore, a pharmaceutically acceptable salt can have more than onecharged atom in its structure. In this instance the pharmaceuticallyacceptable salt can have multiple counterions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms and/or one or morecounterions.

As used herein, the term “isolated and purified form” means that whenisolated (e.g., from other components of a synthetic organic chemicalreaction mixture), the isolate contains at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or at least 98% of an Aryl Sulfonamide Compoundby weight of the isolate. In one embodiment, the isolate contains atleast 95% of an Aryl Sulfonamide Compound by weight of the isolate.

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide an active compound, particularly anAryl Sulfonamide Compound. Examples of prodrugs include, but are notlimited to, derivatives and metabolites of an Aryl Sulfonamide Compoundthat include biohydrolyzable groups such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues (e.g., monophosphate, diphosphate or triphosphate).Preferably, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6^(th) ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

As used herein, the terms “treat”, “treating” and “treatment” refer tothe eradication or amelioration of a disease or symptoms associated witha disease. In certain embodiments, such terms refer to minimizing thespread or worsening of the disease resulting from the administration ofone or more prophylactic or therapeutic agents to a patient with such adisease.

As used herein, the terms “prevent”, “preventing” and “prevention” referto the prevention of the onset, recurrence or spread of the disease in apatient resulting from the administration of a prophylactic ortherapeutic agent.

The term “effective amount” as used herein refers to an amount of anAryl Sulfonamide Compound or other active ingredient sufficient toprovide a therapeutic or prophylactic benefit in the treatment orprevention of a disease or to delay or minimize symptoms associated witha disease. Further, a therapeutically effective amount with respect toan Aryl Sulfonamide Compound means that amount of therapeutic agentalone, or in combination with other therapies, that provides atherapeutic benefit in the treatment or prevention of a disease. Used inconnection with an Aryl Sulfonamide Compound, the term can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of disease, or enhances the therapeutic efficacy of or synergieswith another therapeutic agent.

As used herein, “syndrome X” refers to a collection of abnormalitiesincluding hyperinsulinemia, obesity, elevated levels of triglycerides,uric acid, fibrinogen, small dense LDL particles and plasminogenactivator inhibitor 1 (PAI-1), and decreased levels of HDL cholesterol.Syndrome X is further meant to include metabolic syndrome.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity of, forexample, 11β-HSD1. “Modulation”, as used herein in its various forms, isintended to encompass inhibition, antagonism, partial antagonism,activation, agonism and/or partial agonism of the activity associatedwith 11β-HSD1. 11β-HSD1 inhibitors are compounds that, e.g., bind to,partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. 11β-HSD1 activators are compounds that, e.g., bind to,stimulate, increase, open, activate, facilitate, enhance activation,sensitize or up regulate signal transduction. The ability of a compoundto modulate 11β-HSD1 can be demonstrated in an enzymatic assay or acell-based assay. For example, the inhibition of 11β-HSD1 may decreasecortisol levels in a patient and/or increase cortisone levels in apatient by blocking the conversion of cortisone to cortisol.Alternatively, the inhibition of 11β-HSD2 can increase cortisol levelsin a patient and/or decrease cortisone levels in a patient by blockingthe conversion of cortisol to cortisone.

A “patient” includes an animal (e.g., cow, horse, sheep, pig, chicken,turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig), in oneembodiment a mammal such as a non-primate and a primate (e.g., monkeyand human), and in another embodiment a human. In a preferredembodiment, a patient is a human. In specific embodiments, the patientis a human infant, child, adolescent or adult.

The term “HSD” as used herein, refers to hydroxysteroid dehydrogenaseenzymes in general, including, but not limited to,11-beta-hydroxysteroid dehydrogenases (11β-HSDs), 17-beta-hydroxysteroiddehydrogenases (17β-HSDs), 20-alpha-hydroxysteroid dehydrogenases(20α-HSDs), 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs), and allisoforms thereof.

The term “11β-HSD1” as used herein, refers to the 11-beta-hydroxysteroiddehydrogenase type 1 enzyme, variant, or isoform thereof. 11β-HSD1variants include proteins substantially homologous to native 11β-HSD1,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 11β-HSD1derivatives, homologs and fragments). The amino acid sequence of a11β-HSD1 variant preferably is at least about 80% identical to a native11β-HSD1, more preferably at least about 90% identical, and mostpreferably at least about 95% identical.

The term “11β-HSD2” as used herein, refers to the 11-beta-hydroxysteroiddehydrogenase type 2 enzyme, variant, or isoform thereof. 11β-HSD2variants include proteins substantially homologous to native 11β-HSD2,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 11β-HSD2derivatives, homologs and fragments). The amino acid sequence of a11β-HSD2 variant preferably is at least about 80% identical to a native11β-HSD2, more preferably at least about 90% identical, and mostpreferably at least about 95% identical. (see Bart et al., J. Med.Chem., 2002, 45:3813-3815).

The term “17β-HSD3” as used herein, refers to the 17-beta-hydroxysteroiddehydrogenase type 3 enzyme, variant, or isoform thereof. 17β-HSD3variants include proteins substantially homologous to native 17β-HSD3,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 17β-HSD3derivatives, homologs and fragments). The amino acid sequence of a17β-HSD3 variant preferably is at least about 80% identical to a native17β-HSD3, more preferably at least about 90% identical, and mostpreferably at least about 95% identical.

As used herein, the term “HSD-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of a hydroxysteroid dehydrogenase enzyme (HSD).Favorable responses to HSD modulation include alleviation or abrogationof the disease and/or its attendant symptoms, inhibition of the disease,i.e., arrest or reduction of the development of the disease, or itsclinical symptoms, and regression of the disease or its clinicalsymptoms. An HSD-responsive condition or disease may be completely orpartially responsive to HSD modulation. An HSD-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, HSD activity and at least partially responsive toor affected by HSD modulation (e.g., an HSD inhibitor results in someimprovement in patient well-being in at least some patients).Inappropriate HSD functional activity might arise as the result of HSDexpression in cells which normally do not express HSD, decreased HSDexpression or increased HSD expression. An HSD-responsive condition ordisorder may include condition or disorder mediated by any HSD orisoform thereof.

As used herein, the term “11β-HSD1-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 11β-HSD1 activity. Favorable responses to11β-HSD1 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An11β-HSD1-responsive condition or disease may be completely or partiallyresponsive to 11β-HSD1 modulation. An 11β-HSD1-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 11β-HSD1 activity and at least partially responsiveto or affected by 11β-HSD1 modulation (e.g., a 11β-HSD1 inhibitorresults in some improvement in patient well-being in at least somepatients). Inappropriate 11β-HSD1 functional activity might arise as theresult of 11β-HSD1 expression in cells which normally do not express11β-HSD1, decreased 11β-HSD1 expression or increased 11β-HSD1expression. A 11β-HSD1-responsive condition or disorder may include a11β-HSD1-mediated condition or disorder.

As used herein, the term “11β-HSD2-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 11β-HSD2 activity. Favorable responses to11β-HSD2 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An11β-HSD2-responsive condition or disease may be completely or partiallyresponsive to 11β-HSD2 modulation. An 11β-HSD2-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 11β-HSD2 activity and at least partially responsiveto or affected by 11β-HSD2 modulation (e.g., a 11β-HSD2 inhibitorresults in some improvement in patient well-being in at least somepatients).

As used herein, the term “17β-HSD3-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 17β-HSD3 activity. Favorable responses to17β-HSD3 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An17β-HSD3-responsive condition or disease may be completely or partiallyresponsive to 17β-HSD3 modulation. An 17β-HSD3-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 17β-HSD3 activity and at least partially responsiveto or affected by 17β-HSD3 modulation (e.g., a 17β-HSD3 inhibitorresults in some improvement in patient well-being in at least somepatients). Inappropriate 17β-HSD3 functional activity might arise as theresult of 17β-HSD3 expression in cells which normally do not express17β-HSD3, decreased 17β-HSD3 expression or increased 17β-HSD3expression. A 17β-HSD3-responsive condition or disorder may include a17β-HSD3-mediated condition or disorder.

As used herein, the term “HSD-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, activity of ahydroxysteroid dehydrogenase (HSD). An HSD-mediated condition ordisorder may be completely or partially characterized by inappropriateHSD activity. However, an HSD-mediated condition or disorder is one inwhich modulation of an HSD results in some effect on the underlyingcondition or disease (e.g., an HSD inhibitor results in some improvementin patient well-being in at least some patients).

As used herein, the term “11β-HSD1-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 11β-HSD1activity. A 11β-HSD1-mediated condition or disorder may be completely orpartially characterized by inappropriate 11β-HSD1 activity. However, a11β-HSD1-mediated condition or disorder is one in which modulation of11β-HSD1 results in some effect on the underlying condition or disease(e.g., a 11β-HSD1 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, the term “11β-HSD2-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 11β-HSD2activity. A 11β-HSD2-mediated condition or disorder may be completely orpartially characterized by inappropriate 11β-HSD2 activity. However, a11β-HSD2-mediated condition or disorder is one in which modulation of11β-HSD2 results in some effect on the underlying condition or disease(e.g., a 11β-HSD2 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, the term “17β-HSD3-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 17β-HSD3activity. A 17β-HSD3-mediated condition or disorder may be completely orpartially characterized by inappropriate 17β-HSD3 activity. However, a17β-HSD3-mediated condition or disorder is one in which modulation of17β-HSD3 results in some effect on the underlying condition or disease(e.g., a 17β-HSD3 inhibitor results in some improvement in patientwell-being in at least some patients).

The following abbreviations are used herein and have the indicateddefinitions: DMEM is Dulbecco's Modified Eagle Medium; Et₃N istriethylamine; EtOAc is ethyl acetate; MeOH is methanol; MS is massspectrometry; NMR is nuclear magnetic resonance; PBS isphosphate-buffered saline; SPA is scintillation proximity assay; THF istetrahydrofuran; and TMS is trimethylsilyl.

COMPOUNDS OF THE INVENTION

The present invention provides compounds of Formula (I) as well as theirpharmaceutically acceptable salts, solvates, stereoisomers, or prodrugsthereof, collectively referred to as the “The Aryl SulfonamideCompounds.”

In formula (I), R¹ is selected from —OH, (C₁-C₈)alkyl and(C₁-C₈)haloalkyl; R² and R³ are independently selected from halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl; and N^(cyc)is a nitrogen heterocycle having a formula selected from formula (a),formula (b), formula (c) and formula (d):

In formulae (a) through (d), the substituents, subscripts and variablehave the following meanings:

In formula (a), R^(2a), R^(2a′) and R^(5a) are each independentlyselected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR″, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally R^(2a) and R^(2a′) are combinedto form an oxo (═O) or thiono (═S) group when at least one of R^(3a) andR^(4a) is other than H; and wherein when R^(5a) is —C(O)R′, —C(O)OR′ or—OR″ then at least one of R^(2a), R^(2a′), R^(3a) and R^(4a) is otherthan H; R^(3a) and R^(4a) are each independently selected from H,halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—C(O)N(R′)₂, —OR″, —OC(O)R′, —NR′C(O)OR″, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally two adjacent R^(3a), R^(4a) andR^(5a) members are combined to form a benzene or pyridine ring, fused tothe remainder of N^(cyc); and within formula (a), at least one ofR^(2a), R^(2a′), R^(3a), R^(4a) and R^(5a) is other than H.

In formula (b), R^(2b), R^(2b′) and R^(6b) are each independentlyselected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally R^(2b) and R^(2b′) are combinedto form an oxo (═O) or thiono (═S) group when at least one of R^(3b),R^(4b) and R^(5b) is other than H; R^(3b), R^(4b) and R^(5b) are eachindependently selected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,—C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″,—SO₂R″, —SO₂N(R′)₂, —N(R′)₂, and —NR′C(O)R′; and optionally two adjacentR^(3b), R^(4b), R^(5b) and R^(6b) members are combined to form a benzeneor pyridine ring, fused to the remainder of N^(cyc); and within formula(b), at least one of R^(2b), R^(2b′), R^(3b), R^(4b), R^(5b) and R^(6b)is other than H.

In formula (c), X is O or S(O)_(k) wherein k is an integer of from 0 to2; R^(2c), R^(2c′) and R^(6c) are each independently selected from H,halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″,—SO₂N(R′)₂, —N(R′)₂, and —NR′C(O)R′; and optionally R^(2c) and R^(2c′)are combined to form an oxo (═O) or thiono (═S) group when at least oneof R^(3c) and R^(4c) is other than H; R^(3c) and R^(5c) are eachindependently selected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,—C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂,—S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂, and —NR′C(O)R′; and optionally twoadjacent R^(2c), R^(2c′), R^(3c), R^(5c) and R^(6c) members are combinedto form a benzene or pyridine ring, fused to the remainder of N^(cyc);and within formula (c), at least one of R^(2c), R^(2c′), R^(3c), R^(5c)and R^(6c) is other than H.

In formula (d), the subscript m is an integer of from 1 to 6; thesubscript n is 2 or 3; R^(2d) and R^(2d′) are each independentlyselected from H, halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂ and —NR′C(O)R′; and optionally R^(2d) and R^(2d′) are combinedto form an oxo (═O) or thiono (═S) group when at least one of R^(d) isother than H; each R^(d) is independently selected from H, halogen, —CN,—NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally two adjacent R^(d) members arecombined to form a benzene or pyridine ring, fused to the remainder ofN^(cyc); and within formula (d), at least one of R^(2d), R^(2d′) andR^(d) is other than H.

For each of formulae (a)-(d), any fused benzene or pyridine ring portionof N^(cyc) is optionally substituted with from one to four membersselected from halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″,—SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′. Additionally, in these formulae,each occurrence of R′ is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, ortwo R′ groups, when attached to the same nitrogen atom, can be combinedwith the nitrogen atom to which they are attached to form a heterocycleor heteroaryl group; and each occurrence of R″ is independently(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl or aryl(C₁-C₆)alkyl.

Additionally, when N^(cyc) is formula (a), and R^(2a) and R^(2a′) areeach H, then R^(5a) is other than phenyl, furyl, thienyl or pyridyl.Still further, in formula (I), the Aryl Sulfonamide Compounds are otherthan4-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-3,4-dihydro-N,N-dipropyl-2H-1,4-Benzoxazine-6-ethanamineor its salt (Registry No. 144-62-7);N-[[(3R)-4-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-1,1-dioxido-3-thiomorpholinyl]carbonyl]-L-Tyrosine,1,1-dimethylethyl ester, dimethylcarbamate (Registry No. 220544-72-9);andN-[[(3R)-4-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-1,1-dioxido-3-thiomorpholinyl]carbonyl]-L-Tyrosine,dimethylcarbamate (Registry No. 220545-63-1).

Within formula (I), one set of embodiments are those in which R¹ isselected from —OH, (C₁-C₈)alkyl and (C₁-C₈)haloalkyl; and R² and R³ areindependently selected from halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl. Preferredare those embodiments in which R¹ is selected from —OH, (C₁-C₄)alkyl and(C₁-C₄)haloalkyl; and R² and R³ are each independently selected from(C₁-C₄)alkyl and (C₁-C₄)haloalkyl. In a particularly preferred group ofembodiments, R¹ is —OH, R² is —CH₃ and R³ is CF₃. In anotherparticularly preferred group of embodiments, each of R¹, R² and R³ is—CH₃. In still another particularly preferred group of embodiments, R¹is —OH, and R² and R³ are each CF₃. Each of the preferred groups ofembodiments is similarly preferred when combined with specific and/orpreferred groups of embodiments below.

In one group of embodiments, N^(cyc) is a group of formula (a). Withinformula (a), a preferred group of embodiments are those in which each ofR^(2a), R^(2a′) and R^(5a) are H. Still further preferred are thoseembodiments in which one of R^(3a) and R^(4a) is a selected from(C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl. Another group of preferredembodiments are those in which R^(4a) and R^(5a) are combined to form afused benzene ring.

In another group of embodiments, N^(cyc) is a group of formula (b).Within formula (b), one group of embodiments are those in which at leastone of R^(2b), R^(2b′) and R^(6b) is (C₁-C₈)alkyl or(C₂-C₈)hydroxyalkyl. For this group of embodiments, preferred alkyl andhydroxyalkyl groups are methyl, ethyl, propyl, hydroxyethyl andhydroxylpropyl. In another group of embodiments, each of R^(3b), R^(4b)and R^(5b) is H, and R^(6b) is selected from heteroaryl andheteroaryl(C₁-C₄)alkyl. Within this group of embodiments, the heteroarylgroup is preferably a five- or six-membered heteroaryl group such as 2-,3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-pyrazolyl, 1-imidazolyl, andthe like. Preferably, R^(6b) is selected from 2-, 3- or 4-pyridyl. Inyet another group of embodiments, at least one of R^(3b), R^(4b) andR^(5b) is halogen. In still another group of embodiments, R^(4b) andR^(5b) or R^(5b) and R^(6b) are combined to form a fused benzene orpyridine ring. In another group of embodiments, one of R^(3b), R^(4b),R^(5b) or R^(6b) is heterocyclyl.

In another group of embodiments, N^(cyc) is a group of formula (c).Within formula (c), one group of embodiments are those in which X is O.In another group of embodiments, X is S. In still another group ofembodiments, at least one of R^(2c), R^(2c′) and R^(6c) is (C₁-C₈)alkyl.

In another group of embodiments, N^(cyc) is a group of formula (d).Within formula (d), one group of embodiments are those in which thesubscript n is 2. Another group of embodiments are those in which thesubscript n is 3. In both of these groups of embodiments, the subscriptm can be 1, 2, 3, 4, 5 or 6. One of skill in the art will appreciatethat other carbon atoms on the seven or eight-membered ring that are notsubstituted by R^(2d), R^(2d′) or R^(d) will have hydrogen atomsattached.

The Aryl Sulfonamide Compounds can have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. This inventionrelates to the use of all optical isomers and stereoisomers of the ArylSulfonamide Compounds, and mixtures thereof, and to all pharmaceuticalcompositions and methods of treatment that may employ or contain them.

It should be noted that racemates, racemic mixtures, and stereoisomers,particularly diastereomeric mixtures or diastereomerically purecompounds and enantiomers or enantiomerically pure compounds of theabove are all encompassed.

Particularly preferred compounds of the invention are provided below:

The present invention also provides compositions comprising atherapeutically effective amount of an Aryl Sulfonamide Compound ofFormula (I) and a pharmaceutically acceptable vehicle, carrier, diluentor excipient.

The invention further provides Aryl Sulfonamide Compounds of Formula (I)that are in isolated and purified form.

The invention provides methods for treating diabetes comprisingadministering to a patient in need thereof a therapeutically effectiveamount of an Aryl Sulfonamide Compound of Formula (I).

The invention also provides methods for treating obesity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of an Aryl Sulfonamide Compound of Formula (I).

The invention further provides methods for treating an HSD-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

The invention further provides methods for treating an 11β-HSD1-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

The invention further provides methods for treating an 11β-HSD2-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

The invention further provides methods for treating an 17β-HSD3-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

The invention further provides methods for treating an HSD-responsivecondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of an Aryl SulfonamideCompound of Formula (I).

The invention further provides methods for treating an11β-HSD1-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of an ArylSulfonamide Compound of Formula (I).

The invention further provides methods for treating an11β-HSD2-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of an ArylSulfonamide Compound of Formula (I).

The invention further provides methods for treating an17β-HSD3-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of an ArylSulfonamide Compound of Formula (I).

Preparation of the Aryl Sulfonamide Compounds of Formula I

Those skilled in the art will recognize that there are a variety ofmethods available to synthesize molecules represented in the claims. Ingeneral, useful methods for synthesizing compounds represented in theclaims consist of three parts, which may be done in any order: formationof a sulfonamide linkage, installation of a —CR¹R²R³ group andinstallation or modification of functional groups appended to theN^(cyc) ring(s). The synthesis of single enantiomers and diastereomersmay be accomplished via separation of enantiomers via chiral phase HPLC,asymmetric synthesis, or formation of chiral diastereomers via use ofchiral auxiliaries.

A variety of the methods described above have been used to preparecompounds of the invention, some of which are exemplified in theexamples.

Pharmaceutical Compositions

Pharmaceutical compositions and single unit dosage forms comprising anAryl Sulfonamide Compound, or a pharmaceutically acceptablestereoisomer, prodrug, salt, solvate, hydrate, or clathrate thereof, arealso encompassed by the invention. Individual dosage forms of theinvention may be suitable for oral, mucosal (including sublingual,buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous,intramuscular, bolus injection, intraarterial, or intravenous),transdermal, or topical administration.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of inflammation or a related disease may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed by this invention will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore carriers, excipients or diluents. Suitable excipients are wellknown to those skilled in the art of pharmacy, and non-limiting examplesof suitable excipients are provided herein. Whether a particularexcipient is suitable for incorporation into a pharmaceuticalcomposition or dosage form depends on a variety of factors well known inthe art including, but not limited to, the way in which the dosage formwill be administered to a patient. For example, oral dosage forms suchas tablets may contain excipients not suited for use in parenteraldosage forms. The suitability of a particular excipient may also dependon the specific active ingredients in the dosage form.

This invention further encompasses anhydrous (e.g., <1% water)pharmaceutical compositions and dosage forms comprising activeingredients, since water can facilitate the degradation of somecompounds. For example, the addition of water (e.g., 5%) is widelyaccepted in the pharmaceutical arts as a means of simulating long-termstorage in order to determine characteristics such as shelf-life or thestability of formulations over time. See, e.g., Jens T. Carstensen, DrugStability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y.,1995, pp. 379-80. In effect, water and heat accelerate the decompositionof some compounds. Thus, the effect of water on a formulation can be ofgreat significance since moisture and/or humidity are commonlyencountered during manufacture, handling, packaging, storage, shipment,and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

The Aryl Sulfonamide Compound can be administered to a mammal (human,mouse, rat, rabbit, dog, cat, bovine, pig, monkey etc.) as an 11β-HSD1modulator, a prophylactic or therapeutic drug of diabetes, aprophylactic or therapeutic drug of diabetic complication (retinopathy,nephropathy, neuropathy, cardiac infarction and cerebral infarctionbased on arteriosclerosis etc.), a prophylactic or therapeutic drug ofhyperlipemia, a prophylactic or therapeutic drug of obesity,neurodegenerative disease and the like, or a prophylactic or therapeuticdrug of diseases mediated by 11β-HSD1.

The Aryl Sulfonamide Compound can be administered to a mammalconcurrently with an additional therapeutic agent for the treatment of adisease, such as diabetes or obesity, with the aim of the prophylaxis ortreatment of a disease. As such, the Aryl Sulfonamide Compounds of thepresent invention can be administered in combination with othertherapeutic agents for the treatment or prevention of numerous diseases,including, but not limited to, diabetes and obesity.

Depending on the disease to be treated and the patient's condition, thecompounds of the invention may be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal,local) routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. The invention alsocontemplates administration of the compounds of the invention in a depotformulation, in which the active ingredient is released over a definedtime period.

In the case of a combined administration, the Aryl Sulfonamide Compoundmay be administered simultaneously with other another therapeutic agentthat is useful for the treatment or prevention of diabetes, obesity orother disease or may be administered at a time prior to or subsequent toanother therapeutic agent. In the case of combined administration, apharmaceutical composition containing the Aryl Sulfonamide Compound andan additional therapeutic agent can be administered. Alternatively, apharmaceutical composition containing the Aryl Sulfonamide Compound anda pharmaceutical composition containing an additional therapeutic agentmay be administered separately. The administration routes of respectivepharmaceutical compositions may be the same or different.

In the case of a combined administration, the Aryl Sulfonamide Compoundmay be administered at a dose of 50 mg to 800 mg per administration,which is given once to several times a day. In addition, the compoundmay be administered at a smaller dose. The combined pharmaceutical agentcan be administered at a dose generally employed for the prophylaxis ortreatment of diabetes or obesity or at a smaller dose than that.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise anAryl Sulfonamide Compound, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate, polymorph or prodrug thereof. In thetreatment or prevention of diabetes, obesity, glaucoma, osteoporosis,cognitive disorders, immune disorders, depression or other conditions ordisorders associated with the modulation of an hydroxysteroiddehydrogenase, an appropriate dosage level will generally be from about0.001 to about 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be from about 0.01 to about 25 mg/kg per day; more preferably fromabout 0.05 to about 10 mg/kg per day. A suitable dosage level may befrom about 0.01 to about 25 mg/kg per day, about 0.05 to about 10 mg/kgper day, or about 0.1 to about 5 mg/kg per day. Within this range thedosage may be from about 0.005 to about 0.05, about 0.05 to about 0.5 orabout 0.5 to about 5.0 mg/kg per day lie within the range of from about0.1 mg to about 2000 mg per day, given as a single once-a-day dose inthe morning but preferably as divided doses throughout the day takenwith food. More preferably, the daily dose is administered twice dailyin equally divided doses. Preferably, a daily dose range should be fromabout 5 mg to about 500 mg per day, more preferably, between about 10 mgand about 200 mg per day. In managing the patient, the therapy should beinitiated at a lower dose, perhaps from about 1 mg to about 25 mg, andincreased if necessary up to from about 200 mg to about 2000 mg per dayas either a single dose or divided doses, depending on the patient'sglobal response.

For multidrug therapy, the weight ratio of the compound of the inventionto the second active ingredient may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used. Thus, for example, when a compound of the invention iscombined with an NSAID, the weight ratio of the compound of theinvention to the NSAID will generally range from about 1000:1 to about1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the invention and other active ingredients will generallyalso be within the aforementioned range, but in each case, an effectivedose of each active ingredient should be used.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

For oral administration, the compositions are preferably provided in theform of tablets containing about 1 to about 1000 milligrams of theactive ingredient. In other embodiments, the compositions are providedin provided in the form of tablets containing about 1.0, about 5.0,about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0,about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0,or about 1000.0 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

Controlled-release pharmaceutical products can improve drug therapy overthat achieved by their non-controlled counterparts. Ideally, the use ofan optimally designed controlled-release preparation in medicaltreatment is characterized by a minimum of drug substance being employedto cure or control the condition in a minimum amount of time. Advantagesof controlled-release formulations include extended activity of thedrug, reduced dosage frequency, and increased patient compliance. Inaddition, controlled-release formulations can be used to affect the timeof onset of action or other characteristics, such as blood levels of thedrug, and can thus affect the occurrence of side (e.g., adverse)effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intra-arterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions. For example, lyophilizedsterile compositions suitable for reconstitution into particulate-freedosage forms suitable for administration to humans.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Parenteral dosage forms are preferred for the methods of preventing,treating or managing disease in a cancer patient.

Transdermal and Topical Dosage Forms

Transdermal and topical dosage forms of the invention include, but arenot limited to, creams, lotions, ointments, gels, solutions, emulsions,suspensions, or other forms known to one of skill in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, EastonPa. (1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal and topical dosage formsencompassed by this invention are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants also can be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Mucosal Dosage Forms and Lung Delivery

Mucosal dosage forms of the invention include, but are not limited to,ophthalmic solutions, sprays and aerosols, or other forms known to oneof skill in the art. See, e.g., Remington's Pharmaceutical Sciences,18th eds., Mack Publishing, Easton Pa. (1990); and Introduction toPharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia(1985). Dosage forms suitable for treating mucosal tissues within theoral cavity can be formulated as mouthwashes or as oral gels. In oneembodiment, the aerosol comprises a carrier. In another embodiment, theaerosol is carrier free.

A compound of the invention can also be administered directly to thelung by inhalation (see e.g., Tong et al., International Publication No.WO 97/39745; Clark et al, International Publication No. WO 99/47196,which are herein incorporated by reference). For administration byinhalation, an Aryl Sulfonamide Compound can be conveniently deliveredto the lung by a number of different devices. For example, a MeteredDose Inhaler (“MDI”) which utilizes canisters that contain a suitablelow boiling propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas can be used to deliver an Aryl Sulfonamide Compounddirectly to the lung. MDI devices are available from a number ofsuppliers such as 3M Corporation, Aventis, Boehringer Ingleheim, ForestLaboratories, Glaxo-Wellcome, Schering Plough and Vectura.

Alternatively, a Dry Powder Inhaler (DPI) device can be used toadminister an Aryl Sulfonamide Compound to the lung (See, e.g., Raleighet al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40,397, which is herein incorporated by reference). DPI devices typicallyuse a mechanism such as a burst of gas to create a cloud of dry powderinside a container, which can then be inhaled by the patient. DPIdevices are also well known in the art and can be purchased from anumber of vendors which include, for example, Fisons, Glaxo-Wellcome,Inhale Therapeutic Systems, ML Laboratories, Qdose and Vectura. Apopular variation is the multiple dose DPI (“MDDPI”) system, whichallows for the delivery of more than one therapeutic dose. MDDPI devicesare available from companies such as AstraZeneca, GlaxoWellcome, IVAX,Schering Plough, SkyePharma and Vectura. For example, capsules andcartridges of gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch for these systems.

Another type of device that can be used to deliver an Aryl SulfonamideCompound to the lung is a liquid spray device supplied, for example, byAradigm Corporation. Liquid spray systems use extremely small nozzleholes to aerosolize liquid drug formulations that can then be directlyinhaled into the lung.

In a preferred embodiment, a nebulizer device is used to deliver an ArylSulfonamide Compound to the lung. Nebulizers create aerosols from liquiddrug formulations by using, for example, ultrasonic energy to form fineparticles that can be readily inhaled (See e.g., Verschoyle et al.,British J Cancer, 1999, 80, Suppl 2, 96, which is herein incorporated byreference). Examples of nebulizers include devices supplied bySheffield/Systemic Pulmonary Delivery Ltd. (See, Armer et al., U.S. Pat.No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619; van derLinden et al., U.S. Pat. No. 5,970,974, which are herein incorporated byreference), Aventis and Batelle Pulmonary Therapeutics. Inhaledcompounds, delivered by nebulizer devices, are currently underinvestigation as treatments for aerodigestive cancer (Engelke et al.,Poster 342 at American Association of Cancer Research, San Francisco,Calif., Apr. 1-5, 2000) and lung cancer (Dahl et al., Poster 524 atAmerican Association of Cancer Research, San Francisco, Calif., Apr.1-5, 2000).

In a particularly preferred embodiment, an electrohydrodynamic (“EHD”)aerosol device is used to deliver an Aryl Sulfonamide Compound to thelung. EHD aerosol devices use electrical energy to aerosolize liquiddrug solutions or suspensions (see e.g., Noakes et al., U.S. Pat. No.4,765,539; Coffee, U.S. Pat. No. 4,962,885; Coffee, InternationalPublication No. WO 94/12285; Coffee, International Publication No. WO94/14543; Coffee, International Publication No. WO 95/26234, Coffee,International Publication No. WO 95/26235, Coffee, InternationalPublication No. WO 95/32807, which are herein incorporated byreference). The electrochemical properties of the compound of theinvention formulation may be important parameters to optimize whendelivering this drug to the lung with an EHD aerosol device and suchoptimization is routinely performed by one of skill in the art. EHDaerosol devices may more efficiently delivery drugs to the lung thanexisting pulmonary delivery technologies. Other methods ofintra-pulmonary delivery of an Aryl Sulfonamide Compound will be knownto the skilled artisan and are within the scope of the invention.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include an ArylSulfonamide Compound with a pharmaceutically acceptable carrier.Preferably, the pharmaceutically acceptable carrier is a liquid such asalcohol, water, polyethylene glycol or a perfluorocarbon. Optionally,another material may be added to alter the aerosol properties of thesolution or suspension of an Aryl Sulfonamide Compound. Preferably, thismaterial is liquid such as an alcohol, glycol, polyglycol or a fattyacid. Other methods of formulating liquid drug solutions or suspensionsuitable for use in aerosol devices are known to those of skill in theart (See, e.g., Biesalski, U.S. Pat. Nos. 5,112,598; Biesalski,5,556,611, which are herein incorporated by reference). A compound ofthe invention can also be formulated in rectal or vaginal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, an ArylSulfonamide Compound can also be formulated as a depot preparation. Suchlong acting formulations can be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds can be formulated withsuitable polymeric or hydrophobic materials (for example, as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

Other Delivery Systems

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well known examples of delivery vehiclesthat can be used to deliver an Aryl Sulfonamide Compound. Certainorganic solvents such as dimethylsulfoxide can also be employed,although usually at the cost of greater toxicity. A compound of theinvention can also be delivered in a controlled release system. In oneembodiment, a pump can be used (Sefton, CRC Crit. Ref Biomed Eng., 1987,14, 201; Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N.Engl. J. Med, 1989, 321, 574). In another embodiment, polymericmaterials can be used (see Medical Applications of Controlled Release,Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); ControlledDrug Bioavailability, Drug Product Design and Performance, Smolen andBall (eds.), Wiley, New York (1984); Ranger and Peppas, J Macromol. Sci.Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science 1985,228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al.,1989, J. Neurosurg. 71, 105). In yet another embodiment, acontrolled-release system can be placed in proximity of the target ofthe compounds of the invention, e.g., the lung, thus requiring only afraction of the systemic dose (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115 (1984)).Other controlled-release system can be used (see e.g., Langer, Science,1990, 249, 1527).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide mucosal dosage forms encompassed by thisinvention are well known to those skilled in the pharmaceutical arts,and depend on the particular site or method which a given pharmaceuticalcomposition or dosage form will be administered. With that fact in mind,typical excipients include, but are not limited to, water, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof, which arenon-toxic and pharmaceutically acceptable. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, canalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Therapeutic Uses of the Aryl Sulfonamide Compounds

In one aspect, the invention provides methods of treating or preventinga condition or disorder associated with the modulation of hydroxysteroiddehydrogenases by administering to a patient having such a condition ordisorder a therapeutically effective amount of a compound or compositionof the invention. In one group of embodiments, conditions and disorders,including chronic diseases of humans or other species, can be treatedwith modulators, stimulators, or inhibitors of hydroxysteroiddehydrogenases, such as 11β-HSD1.

Treatment or Prevention of Diabetes

Diabetes and diabetic conditions can be treated or prevented byadministration of a therapeutically effective amount of an ArylSulfonamide Compound.

Types of diabetes that can be treated or prevented by administering atherapeutically effective amount of an Aryl Sulfonamide Compound includetype I diabetes mellitus (juvenile onset diabetes, insulindependent-diabetes mellitus or IDDM), type II diabetes mellitus(non-insulin-dependent diabetes mellitus or NIDDM), insulinopathies,diabetes associated with pancreatic disorders, diabetes associated withother disorders (such as Cushing's Syndrome, acromegaly,pheochromocytoma, glucagonoma, primary aldosteronism, andsomatostatinoma), type A and type B insulin resistance syndromes,lipatrophic diabetes, and diabetes induced by β-cell toxins.

In a preferred embodiment, the type of diabetes being treated is type IIdiabetes.

Treatment or Prevention of Obesity

Obesity can be treated or prevented by administration of atherapeutically effective amount of an Aryl Sulfonamide Compound.

Obesity may have genetic, environmental (e.g., expending less energythan is consumed) and regulatory determinants. Obesity includesexogenous, hyperinsulinar, hyperplasmic, hypothyroid, hypothalamic,symptomatic, infantile, upper body, alimentary, hypogonadal, simple andcentral obesity, hypophyseal adiposity and hyperphagia. Metabolicdisorders, such as hyperlidemia and diabetes, and cardiovasculardisorders, such as hypertension and coronary artery disease, arecommonly associated with obesity.

Complications due to obesity may also be treated or prevented byadministering a therapeutically effective amount of an Aryl SulfonamideCompound. Such complications include, but are not limited to, sleepapnea, Pickwickian syndrome, orthopedic disturbances of weight-bearingand non-weight-bearing joints, and skin disorders resulting fromincreased sweat or skin secretions.

Treatment or Prevention of Other Conditions

Other Conditions that can be treated or prevented by administering atherapeutically effective amount of an Aryl Sulfonamide Compoundinclude, but are not limited to any condition which is responsive to themodulation, preferably inhibition, of hydroxysteroid dehydrogenases orspecific isoforms thereof, and thereby benefit from administration ofsuch a modulator. Representative conditions in this regard include, butare not limited to, metabolic disorders and related cardiovascular riskfactors such as syndrome X, polycystic ovarian disease, eating disorders(e.g., anorexia and bulimia), craniopharyngioma, Prader-Willi syndrome,Frohlich's syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia and Cushing's syndrome; diseasesassociated therewith such as hypertension, atherosclerosis, vascularrestenosis, retinopathy and nephropathy; neurologic disorders such asneurodegenerative disease, neuropathy and muscle wasting; cognitivedisorders, such as age-related learning disorders, dementia,neurodegeneration, as well as for improvement of cognitive function insubjects ranging from the severely impaired (e.g., Parkinsons's orAlzheimer's associated dementia) to mildly impaired (e.g.,age-associated memory impairment, drug-induced cognitive impairment) tounimpaired subjects (e.g., cognitive enhancers for the generalpopulation) (see, Sandeep, et al., PNAS, electronically available atwww.pnas.org/cgi/doi/10.1073/pnas.0306996101); androgen and/orestrogen-related disorders such as prostate cancer, colon cancer, breastcancer, benign prostatic hyperplasia, ovarian cancer, uterine cancer,and male pseudohermaphrodism; endometriosis, dementia, depression,psoriasis, glaucoma, osteoporosis, viral infections, inflammatorydisorders, and immune disorders.

Additional Therapeutic Agents

In one embodiment, the present methods for treating or preventingfurther comprise the administration of a therapeutically effectiveamount of another therapeutic agent useful for treating or preventingthe diseases or disorders disclosed herein. In this embodiment, the timein which the therapeutic effect of the other therapeutic agent isexerted overlaps with the time in which the therapeutic effect of theAryl Sulfonamide Compound is exerted.

The compounds of the invention can be combined or used in combinationwith other agents useful in the treatment, prevention, suppression oramelioration of the conditions or disorders for which compounds of theinvention are useful, including diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders, depression andthose pathologies noted above.

Such other agents, or drugs, may be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with anAryl Sulfonamide Compound. When an Aryl Sulfonamide Compound is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe invention is preferred. Accordingly, the pharmaceutical compositionsof the invention include those that also contain one or more otheractive ingredients or therapeutic agents, in addition to an ArylSulfonamide Compound.

In one embodiment, for the treatment or prevention of diabetes, an ArylSulfonamide Compound can be administered with another therapeutic agent,including, but not limited to, anti-diabetic agents such as insulin,inhaled insulin (Exubera®), insulin mimetics, insulin secretogues,sulfonylureas (e.g., glyburide, meglinatide, glimepiride, gliclazide,glipizide, gliquidone, chloropropresponsivemide, tolbutamide,acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid,glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide,phenbutamide, tolcylamide and tolazamide), biguanides (e.g., metformin(Glucophage®)), α-glucosidase inhibitors (e.g., acarbose, voglibose andmiglitol), thiazolidinone compounds (e.g., rosiglitazone (Avandia®),troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) andenglitazone), prandial glucose regulators (e.g., repaglinide andnateglinide) and glucagon receptor antagonists.

In another embodiment, for the treatment or prevention of obesity, anAryl Sulfonamide Compound can be administered with another therapeuticagent, including, but not limited to, β3 adrenergic receptor agonists,leptin or derivatives thereof, neuropeptide Y (e.g., NPY5) antagonists,and mazindol.

Examples of other therapeutic agents that may be combined with an ArylSulfonamide Compound, either administered separately or in the samepharmaceutical compositions, include, but are not limited to: (i)cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g.,lovastatin, simvastatin (Zocor®), pravastatin, fluvastatin, atorvastatin(Lipitor®) and other statins), bile acid sequestrants (e.g.,cholestyramine and colestipol), vitamin B₃ (also known as nicotinicacid, or niacin), vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin),fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate andbenzafibrate), probucol, nitroglycerin, and inhibitors of cholesterolabsorption (e.g., beta-sitosterol and acylCoA-cholesterolacyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthaseinhibitors, squalene epoxidase inhibitors and squalene synthetaseinhibitors; (ii) antithrombotic agents, such as thrombolytic agents(e.g., streptokinase, alteplase, anistreplase and reteplase), heparin,hirudin and warfarin derivatives, β-blockers (e.g., atenolol), βadrenergic agonists (e.g., isoproterenol), angiotensin II antagonists,ACE inhibitors and vasodilators (e.g., sodium nitroprusside, nicardipinehydrochloride, nitroglycerin and enaloprilat); (iii) PPAR agonists,e.g., PPARγ and PPAR_(δ) agonists; (iv) DP antagonists; (v) lubricantsor emollients such as petrolatum and lanolin, keratolytic agents,vitamin D₃ derivatives (e.g., calcipotriene and calcipotriol(Dovonex®)), PUVA, anthralin (Drithrocreme®), etretinate (Tegison®) andisotretinoin; (vi) glaucoma therapies such as cholinergic agonists(e.g., pilocarpine and carbachol), cholinesterase inhibitors (e.g.,physostigmine, neostigmine, demacarium, echothiophate iodide andisofluorophate), carbonic anhydrase inhibitors (e.g., acetazolamide,dichlorphenamide, methazolamide, ethoxzolamide and dorzolamide),non-selective adrenergic agonists (e.g., epinephrine and dipivefrin),α₂-selective adrenergic agonists (e.g., apraclonidine and brimonidine),β-blockers (e.g., timolol, betazolol, levobunolol, carteolol andmetipranolol), prostaglandin analogs (e.g., latanoprost) and osmoticdiuretics (e.g., glycerin, mannitol and isosorbide); corticosteroids,such as beclomethasone, methylprednisolone, betamethasone, prednisone,prenisolone, dexamethasone, fluticasone and hydrocortisone, andcorticosteroid analogs such as budesonide; (vii) immunosuppressants suchas cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus(FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil(CellCept®); (viii) non-steroidal antiinflammatory agents (NSAIDs) suchas propionic acid derivatives (e.g., alminoprofen, benoxaprofen,bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen),acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac,clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacinand zomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetylsalicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone); (ix) cyclooxygenase-2 (COX-2)inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (xi)inhibitors of phosphodiesterase type IV (PDE-IV); (xii) opioidanalgesics such as codeine, fentanyl, hydromorphone, levorphanol,meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene,buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine; (xiii)a hepatoprotective agent; and (xiv) other compounds such as5-aminosalicylic acid and prodrugs thereof.

The weight ratio of the compound of the invention to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when an Aryl Sulfonamide Compound is combined with an NSAID,the weight ratio of the compound of the invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of an Aryl Sulfonamide Compound andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Kits

The invention encompasses kits that can simplify the administration ofthe Aryl Sulfonamide Compounds or composition of the invention to apatient.

A typical kit of the invention comprises a unit dosage of an ArylSulfonamide Compound. In one embodiment, the unit dosage form is in acontainer, which can be sterile, containing a therapeutically effectiveamount of an Aryl Sulfonamide Compound and a pharmaceutically acceptablevehicle. In another embodiment, the unit dosage form is in a containercontaining a therapeutically effective amount of an Aryl SulfonamideCompound as a lyophilate or pharmaceutically acceptable salt. In thisinstance, the kit can further comprise another container that contains asolution useful for the reconstitution of the lyophilate or dissolutionof the salt. The kit can also comprise a label or printed instructionsfor use of the Aryl Sulfonamide Compounds.

In a further embodiment, the kit comprises a unit dosage form of acomposition of the invention.

Kits of the invention can further comprise one or more devices that areuseful for administering the unit dosage forms of the Aryl SulfonamideCompounds or a composition of the invention. Examples of such devicesinclude, but are not limited to, a syringe, a drip bag, a patch or anenema, which optionally contain the unit dosage forms.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims. Tothis end, it should be noted that one or more hydrogen atoms or methylgroups may be omitted from the drawn structures consistent with acceptedshorthand notation of such organic compounds, and that one skilled inthe art of organic chemistry would readily appreciate their presence.

EXAMPLES

The Aryl Sulfonamide Compounds represented by the formulas of thepresent invention and the methods of making thereof are explained indetail in the following Examples, which are not to be construed aslimiting the invention.

Example A Synthesis of5-chloro-1-(4-tert-butylphenylsulfonyl)-2,3-dihydroindole

5-Chloro-2,3-dihydroindole (148 mg, 0.955 mmol, 1.0 equiv) was dissolvedin 4 mL CH₂Cl₂ followed by the addition of 400 μL triethylamine (2.87mmol, 3.0 equiv) and 200 mg 4-tert-butylsulfonyl chloride (0.859 mmol,0.9 equiv). After stirring for 16 h the reaction mixture was dilutedwith saturated NaHCO₃ and the resulting solution was poured into a 3MEmpore 4415(SD) C18-SD octadecyl hydrophobic cartridge. The organicswhich passed through the cartridge were then concentrated under reducedpressure. Purification by flash chromatography (SiO₂, 0.5% MeOH/CH₂Cl₂)gave the product as a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.75 (d,J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.47 (d, J=19.2 Hz, 1H), 7.24 (m,2H), 3.90 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.4 Hz, 2H), 1.23 (s, 9H).

Example B Synthesis of3-(R)-1-(4-tert-butylphenylsulfonyl)-3-imidazol-1-yl)-pyrrolidine

3-(S)-3-Hydroxy-1-(4-tert-butylphenylsulfonyl)-pyrrolidine (1.93 g, 6.81mmol, 1.0 equiv, prepared as in example A) was dissolved in 50 mL CH₂Cl₂followed by the addition of 1.54 mL Hunig's base (8.85 mmol, 1.3 equiv)and methanesulfonyl chloride (0.58 mL, 7.49 mmol, 1.1 equiv). Afterstirring for 20 min the solution was diluted with saturated NaHCO₃ andextracted 2×CH₂Cl₂. The organics were then washed (1×1 N HCl, 1×saturated NaHCO₃), dried (Na₂SO₄), and concentrated under reducedpressure. Purification via flash chromatography gave 2.19 g of themesylate as a white solid (6.06 mmol, 89%)

The mesylate prepared above (165 mg, 0.456 mmol) was combined with 1 gimidazole in a sealed tube. The sealed tube was then placed in an oilbath and heated to 90° C. After heating for 15 h, the hot solution wasdiluted with H₂O and extracted 2×CH₂Cl₂. The collected organics werewashed, dried (Na₂SO₄), and concentrated under reduced pressure.Purification via flash chromatography (SiO₂, 5% MeOH/CH₂Cl₂) gave thedesired product as a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.76 (d,J=8.6 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 7.57 (s, 1H), 7.02 (t, J=1.2 Hz,1H), 6.83 (s, 1H), 4.76 (ddd, J=5.6, 6.6, 12.2 Hz, 1H), 3.62 (dd, J=6.7,10.6 Hz, 1H), 3.41 (ddd, J=3.7, 6.2, 14.2 Hz, 1H), 2.28 (m, 1H), 2.10(m, 1H), 1.30 (s, 9H).

Example C Synthesis of3-(R)-1-(4-tert-butylphenylsulfonyl)-3-methoxypyrrolidine

Using the general procedure in example A, but substituting3-(R)-3-methoxypyrrolidine for 5-chloro-2,3-dihydroindole, the desiredproduct was obtained as a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.71 (d,J=8.6 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 3.82 (m, 1H), 3.30-3.17 (m, 3H),3.10 (ddd, J=7.5, 9.2, 9.4 Hz, 1H), 2.98 (s, 3H), 1.78 (m, 2H), 1.31 (s,9H).

Example D Synthesis of2-(S)-2-methyl-1-(4-tert-butylphenylsulfonyl)-morpholine

Using the general procedure in example A, but substituting2-(S)-2-methylmorpholine (prepared as in: Powers, J. P., U.S. Pat. No.6,599,911) for 5-chloro-2,3-dihydroindole, the desired product wasobtained as a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.72 (d, J=8.6 Hz,2H), 7.62 (d, J=8.6 Hz, 2H), 3.75 (m, 2H), 3.49 (dd, J=1.2, 11.4 Hz,1H), 3.39-3.30 (m, 2H), 3.25 (dd, J=2.7, 11.6 Hz, 1H), 3.16 (ddd, J=3.2,11.4, 12.3 Hz, 1H), 1.03 (d, J=6.8 Hz, 3H).

Example E Synthesis ofsyn-2,6-dimethyl-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl-sulfonyl)-piperidine

To a solution of 1 mL 2,6-dimethylpiperidine in 1 mL CH₂Cl₂ was added200 mg 4-acetylbenzenesulfonyl chloride (0.915 mmol, 1.0 equiv). Afterstirring for 135 min the reaction mixture was diluted with saturatedNaHCO₃ and the resulting solution was poured into a 3M Empore 4415(SD)C18-SD octadecyl hydrophobic cartridge. The organics which passedthrough the cartridge were then concentrated under reduced pressure.Purification by flash chromatography (SiO₂, 2% MeOH/CH₂Cl₂) gave theproduct as a colorless oil (60 mg, 0.203 mmol, 22%).

The 4-acetylbenzenesulfonamide prepared above (60 mg, 0.203 mmol, 1.0equiv) was dissolved in 1 mL THF followed by the addition of 0.812 mL ofa 0.5 M solution of TMSCF₃ in THF (0.406 mmol, 2.0 equiv). Afterstirring for 5 min, 0.203 mL of a 1.0 M solution of tetrabutylammoniumfluoride (TBAF, 0.203 mmol, 1.0 equiv) was added. The resulting redsolution was allowed to stir for 40 min, diluted with 1.0 N HCl,extracted 2× EtOAc, washed (1× saturated NaHCO₃), dried (MgSO₄), andconcentrated under reduced pressure. Purification by flashchromatography (SiO₂, 1% MeOH/CH₂Cl₂) gave the product as a colorlessoil. ¹H NMR (DMSO, 400 MHz) δ 7.84 (d, J=8.7 Hz, 2H), 7.80 (d, J=8.7 Hz,2H), 6.84 (s, 1H), 4.05 (m, 2H), 1.71 (s, 3H), 1.60 (m, 2H), 1.25 (d,J=7.1 Hz, 6H), 1.20 (m, 2H).

Example F Synthesis of1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-homopiperidine

To a solution of 1 g homopiperidine (10.1 mmol, 7.37 equiv) and 0.5 mLtriethylamine (3.59 mmol, 2.6 equiv) in 20 mL CH₂Cl₂ was added 300 mg4-acetylbenzenesulfonyl chloride (1.37 mmol, 1.0 equiv). After stirringfor 14 h the reaction mixture was diluted with sat. NaHCO₃, extracted(2×CH₂Cl₂), dried (Na₂SO₄), and concentrated under reduced pressure.Purification by flash chromatography (SiO₂, 1% MeOH/CH₂Cl₂) gave theproduct as a white solid 293 mg (1.04 mmol, 76%).

The 4-acetylbenzenesulfonamide prepared above (247 mg, 0.879 mmol, 1.0equiv) was dissolved in 10 mL THF followed by the addition on 3.52 mL ofa 0.5M solution of CF₃TMS in THF. After 5 min, 229 mg oftetrabutylammonium fluoride hydrate (0.879 mmol, 1.0 equiv) was added tothe stirring solution. After stirring 21 h the reaction mixture wasdiluted with sat. NaHCO₃, extracted (2× EtOAc), dried (MgSO₄) andconcentrated under reduced pressure. Purification by flashchromatography (SiO₂, 2% MeOH/CH₂Cl₂) gave the product as a white solid.¹H NMR (DMSO, 400 MHz) δ 7.80 (s, 4H), 6.84 (s, 1H), 3.21 (t, J=5.8 Hz,4H), 1.71 (s, 3H), 1.63 (m, 4H), 1.50 (m, 4H).

Example G Synthesis of2-(R)-2-methyl-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl-sulfonyl)-piperidine

Using the general procedure in examples E and F, but substituting2-(R)-2-methyl-piperidine (prepared as in: Doller, D. et al, TetrahedronAssymetry 1275-1278, 8, 1997) for 2,6-dimethylpiperidine (in example E)or homopiperidine (in example F), the desired product was obtained as awhite solid. ¹H NMR (DMSO, 400 MHz) δ 7.82 (d, J=9.0 Hz, 2H), 7.80 (d,J=9.0 Hz, 2H), 6.84 (s, 1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.96 (ddd,J=2.2, 12.8, 13.5 Hz, 1H), 1.72 (S, 3H), 1.57-1.38 (m, 5H), 1.19 (m,1H), 0.99 (d, J=6.9 Hz, 3H). ESI-MS m/z 352.3 (M+H⁺). Anal. calcd forC₁₅H₂OF₃NO₃S: C, 51.27; H, 5.74; N, 3.99; S, 9.13. Found: C, 51.54; H,5.72; N, 4.08; S, 9.21.

Example H Synthesis of2-(S)-2-methyl-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl-sulfonyl)-piperidine

Using the general procedure in examples E and F, but substituting2-(S)-2-methyl-piperidine (prepared as in: Doller, D. et al, TetrahedronAssymetry 1275-1278, 8, 1997) for 2,6-dimethylpiperidine (in example E)or homopiperidine (in example F), the desired product was obtained as awhite solid. ¹H NMR (DMSO, 400 MHz) δ 7.80 (d, J=9.0 Hz, 2H), 7.79 (d,J=9.0 Hz, 2H), 6.85 (s, 1H), 4.10 (m, 1H), 3.59 (m, 1H), 2.96 (ddd,J=2.6, 13.2, 13.2 Hz, 1H), 1.71 (s, 3H), 1.45 (m, 5H), 1.20 (m, 1H),0.99 (d, J=6.9 Hz, 3H). ESI-MS m/z 352.3 (M+H⁺). Anal. calcd forC₁₅H₂OF₃NO₃S: C, 51.27; H, 5.74; N, 3.99; S, 9.13. Found: C, 51.26; H,5.76; N, 4.08; S, 9.17.

Example I Synthesis of2-ethyl-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-piperidine

Using the general procedure in example F, but substituting2-ethylpiperidine for homopiperidine the desired product was obtained asa light golden oil. ¹H NMR (DMSO, 400 MHz) δ 7.86 (d, J=8.6 Hz, 2H),7.81 (d, J=8.6 Hz, 2H), 6.85 (s, 1H), 3.83 (m, 1H), 3.67 (m, 1H), 2.97(ddd, J=2.3, 13.4, 13.9 Hz, 1H), 1.71 (s, 3H), 1.55 (m, 1H), 1.42 (m,5H), 1.21 (m, 1H), 0.99 (m, 1H), 0.79 (t, J=7.4 Hz, 3H).

Example J Synthesis of1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-piperidine

Using the general procedure in example F, but substituting piperidinefor homopiperidine the desired product was obtained as a white solid. ¹HNMR (DMSO, 400 MHz) δ 7.86 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H),6.88 (s, 1H), 2.89 (t, J=5.3 Hz, 4H), 1.71 (s, 3H), 1.53 (m, 4H), 1.36(m, 2H).

Example K Synthesis of2-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

Using the general procedure in example F, but substituting1,2,3,4-tetrahydroisoquinoline for homopiperidine the desired productwas obtained as a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.88 (d, J=8.8Hz, 2H), 7.84 (d, J=8.8 Hz, 2H), 7.12 (m, 4H), 6.87 (s, 1H), 4.21 (s,2H), 3.33 (m, 2H), 2.85 (t, J=5.9 Hz, 2H), 1.70 (s, 3H).

Example L Synthesis of2-(S)-2-(pyridin-3-yl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-phenylsulfonyl)-piperidine

Using the general procedure in example F, but substituting2-(S)-2-(pyridin-3-yl)-piperidine for homopiperidine the desired productwas obtained as a white solid. ¹H NMR (CHCl₃, 400 MHz) δ 8.46 (m, 2H),7.85 (d, J=8.6 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.8 Hz, 1H),7.24 (m, 1H), 5.28 (m, 1H), 3.82 (d, J=14.3 Hz, 1H), 3.00 (m, 1H), 2.20(d, J=14.8 Hz, 1H), 1.82 (s, 3H), 1.82-1.38 (m, 5H).

Example M Synthesis of1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-1,2,3,4-tetrahydroquinoline

Using the general procedure in example F, but substituting1,2,3,4-tetrahydroquinoline for homopiperidine the desired product wasobtained as a white solid. ¹H NMR (CHCl₃, 300 MHz) δ 7.93 (d, J=6.6 Hz,1H), 7.78 (s, 4H), 7.36 (m, 1H), 7.25 (m, 1H), 7.19 (m, 1H), 3.97 (dd,J=4.6, 5.7 Hz, 2H), 2.58 (m, 2H), 1.82 (dd, J=4.5, 9.3 Hz, 2H), 1.72 (s,3H).

Example N Synthesis of1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-heptamethyleneimine

Using the general procedure in example F, but substitutingheptamethyleneimine for homopiperidine the desired product was obtainedas a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.81 (s, 4H), 6.85 (s, 1H),3.09 (m, 4H), 1.71 (s, 3H), 1.60 (m, 10H).

Example O Synthesis of3-fluoro-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-piperidine

Using the general procedure in example F, but substituting3-fluoropiperidine for homopiperidine the desired product was obtainedas a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.84 (d, J=8.6 Hz, 2H), 7.78(d, J=8.6 Hz, 2H), 6.88 (s, 1H), 4.74 (m, 1H), 3.36 (m, 1H), 3.25 (m,1H), 2.90 (dd, J=11.0, 27.9 Hz, 1H), 2.63 (t, J=10.1 Hz, 1H), 1.72 (s,3H), 1.62 (m, 4H).

Example P Synthesis of1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-2-(2-imidazol-1-yl-ethyl)piperidine

a) To a solution of 1.0 g 2-piperidineethanol (7.73 mmol, 1.11 equiv)and 3.0 mL triethylamine (21.5 mmol, 3.1 equiv) in 20 mL CH₂Cl₂ wasadded 1.52 g 4-acetylbenzenesulfonyl chloride (6.95 mmol, 1.0 equiv).After stirring for 14 h the reaction mixture was diluted with sat.NaHCO₃, extracted (2×CH₂Cl₂), dried (Na₂SO₄), and concentrated underreduced pressure. Purification by flash chromatography (SiO₂, 3%MeOH/CH₂Cl₂) gave the product as a white solid 1.56 g (5.01 mmol, 72%).

The piperidine sulfonamide prepared above (1.19 g, 3.83 mmol, 1.0 equiv)was dissolved in 80 mL CH₂Cl₂ followed by the addition of 0.867 mLHunig's base (4.98 mmol, 1.3 equiv) and 0.325 mL methanesulfonylchloride (4.21 mmol, 1.1 equiv). After stirring for 20 min the reactionmixture was diluted with sat. NaHCO₃ and extracted 2×CH₂Cl₂. The organiclayer was washed (1×1N HCL, 1×sat. NaHCO₃), dried (Na₂SO₄), andconcentrated under reduced pressure. Purification by flashchromatography (SiO₂, 2% MeOH/CH₂Cl₂) gave 1.416 g of the mesylateproduct as a colorless oil (3.64 mmol, 95%).

c) The mesylate prepared above in step b (1.416 g, 3.64 mmol, 1.0 equiv)was dissolved in 20 mL THF followed by the addition of 14.56 mL of a0.5M solution of CF₃TMS in THF (7.28 mmol, 2.0 equiv). The solution wasallowed to stir for 10 min followed by the slow addition of 3.64 mL of a1.0M solution of TBAF in THF (3.64 mmol, 1.0 equiv). After stirring foran additional 10 min the reaction mixture was diluted with sat. NaHCO₃and extracted 3× EtOAc. The organics were washed with 1×1N HCl, 1×sat.NaHCO₃, dried (MgSO₄), and concentrated under reduced pressure.Purification via flash chromatography (SiO₂, 1.5% MeOH/CH₂Cl₂) gave theproduct (Int-1) as a white tacky foam.

d) The mesylate prepared in step c above (Int-1, 293 mg, 0.638 mmol, 1.0equiv) was combine with 1 g imidazole (14.7 mmol, 23.0 equiv) in asealed tube. The tube was placed in a 120° C. bath with stirring for3.75 h, at which time the hot solution was diluted with H₂O. Theresulting aqueous solution was extracted (3×CH₂Cl₂), dried (Na₂SO₄), andconcentrated under reduced pressure. Purification via flashchromatography (SiO₂, 5% MeOH/CH₂Cl₂ gave the product1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenylsulfonyl)-2-(2-imidazol-1-yl-ethyl)piperidineas a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.86 (d, J=8.7 Hz, 2H), 7.80(d, J=8.7 Hz, 2H), 7.61 (d, J=0.8 Hz, 1H), 7.15 (s, 1H), 6.87 (d, J=0.9Hz, 2H), 3.96 (m, 1H), 3.91 (t, J=7.0 Hz, 2H), 3.70 (m, 1H), 3.09 (m,1H), 2.03 (M, 1H), 1.84 (m, 1H), 1.71 (s, 3H), 1.40 (m, 4H), 1.19 (m,1H), 0.99 (m, 1H).

Example Q Synthesis of2-(2-pyrazol-1-yl-ethyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-phenylsulfonyl)-piperidine

Using the procedure in example P, but substituting pyrazole forimidazole in step d (i.e. reacting Int-1 with pyrazole) the desiredproduct was obtained as a white solid. ¹H NMR (DMSO, 400 MHz) δ 7.85 (d,J=8.9 Hz, 2H), 7.79 (d, J=8.9 Hz, 2H), 7.69 (d, J=2.2 Hz, 1H), 7.43 (d,J=1.6 Hz, 1H), 6.86 (s, 1H), 6.21 (t, J=2.0 Hz, 1H), 4.01 (m, 2H), 3.99(m, 1H), 3.68 (m, 1H), 3.02 (t, J=13.5 Hz, 1H), 2.05 (m, 1H), 1.95 (m,1H), 1.71 (s, 3H), 1.40 (m, 4H), 1.19 (m, 1H), 1.00 (m, 1H).

Example R Synthesis of3-(R)-3-(piperidin-1-yl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-phenylsulfonyl)-pyrollidine

a) To a solution of 2.0 g (S)-3-pyrrolidinol (22.95 mmol, 1.05 equiv) in100 mL CH₂Cl₂ was added 4.16 mL Et₃N (29.84 mmol, 1.37 equiv) followedby 4.77 g 4-acetylbenzenesulfonyl chloride (21.81 mmol, 1.0 equiv).After stirring for 22 h the reaction mixture was diluted with sat.NaHCO₃. The solution was then extracted (2×CH₂Cl₂), washed (1×1N HCl,1×sat. NaHCO₃), dried (MgSO₄), and concentrated under reduced pressure.The crude product thus obtained was used directly in the next reaction.

The sulfonamide obtained in step a (2.93 g, 10.89 mmol, 1.0 equiv) wasdissolved in 100 mL CH₂Cl₂ followed by the addition of 2.47 mL Hunig'sbase (14.16 mmol, 1.3 equiv) and 0.927 mL methanesulfonyl chloride(11.98 mmol, 1.1 equiv). After stirring for 30 min the reaction mixturewas diluted with 0.1N HCl and extracted 2×CH₂Cl₂. The organics were thenwashed 1×0.1 N HCl, 1×sat. NaHCO₃, dried (Na₂SO₄), and concentratedunder reduced pressure. Purification via flash chromatography (SiO₂, 2%MeOH/CH₂Cl₂) gave 3.35 g of the mesylate product as a white solid (9.65mmol, 89%).

c) The mesylate obtained in step b (3.35 g, 9.65 mmol, 1.0 equiv) wasdissolved in 50 mL THF followed by the addition of 38.6 mL of a 0.5Msolution of CF₃TMS in THF (19.3 mmol, 2.0 equiv). After stirring for 15min, 9.65 mL of a 1.0M solution of TBAF in THF (9.65 mmol, 1.0 equiv)was added dropwise via syringe. After stirring a further 40 min thereaction mixture was diluted with sat. NaHCO₃ and extracted 2× EtOAc.The organics were then washed (1×0.1N HCl), dried (MgSO₄), andconcentrated under reduced pressure. Purification via flashchromatography (SiO₂, 2% MeOH/CH₂Cl₂) gave 1.009 g of thetrifluoromethylcarbinol as a white solid (2.42 mmol, 25%).

d) Synthesis of3-(R)-3-(piperidin-1-yl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-phenylsulfonyl)-pyrollidine:The trifluoromethylcarbinol prepared in step c (80 mg, 0.192 mmol, 1.0equiv) was combined with 1 g imidazole in a sealed tube followed byheating at 100° C. for 18 h. The resulting hot solution was then dilutedwith sat. NaHCO₃ and extracted 2×CH₂Cl₂. The organics were dried(Na₂SO₄) and concentrated under reduced pressure. Purification via flashchromatography (SiO₂, 5-10% MeOH/CH₂Cl₂) gave the product as a whitesolid. ¹H NMR (DMSO, 400 MHz) δ 7.84 (s, 4H), 6.87 (s, 1H), 3.40 (dd,J=7.1, 9.3 Hz, 1H), 3.27 (ddd, J=3.5, 9.2, 9.4 Hz, 1H), 3.12 (dd, J=8.7,16.5 Hz, 1H), 2.83 (t, J=8.3 Hz, 1H), 2.19 (m, 4H), 1.90 (m, 1H), 1.71(s, 3H), 1.52 (m, 1H), 1.38 (m, 4H), 1.30 (m, 2H).

Example S Synthesis of2-(2-hydroxyethyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-phenylsulfonyl)-piperidine

a) Synthesis of4-(1,1,1,3,3,3-hexafluoropropan-2-ol-2-yl)benzenesulfonyl chloride: To amixture of 4-(hexafluoro-2-hydroxylisopropyl)aniline (15.0 g, 58 mmol),HCl (37% in water, 30 mL), and CH₃COOH (9 mL), NaNO₂ (4.4 g, 64 mmol) inH₂O (5 mL) was added dropwise at −15° C. The temperature of the reactionwas kept at <−5° C. Stirring was continued for 45 min at −5° C. Sulfurdioxide in lecture bottle was introduced into CH₃COOH (30 mL) via apipette for 15 min to make a saturated solution. CuCl (1.43 g, 14.5mmol) was added to the solution at room temperature. While stirring wascontinued, SO₂ introduction was continued for 20 min to make a SO₂—CuClcomplex. At 0° C., the diazotization reaction mixture was added inportions to the SO₂—CuCl complex solution. After addition was complete,stirring was continued for 10 min while the temperature was maintainedunder 10° C. The reaction mixture was then poured onto a 1:1 mixture ofH₂O-ice (500 mL), and stirring was continued until the ice was melted.The mixture was then extracted with Et₂O (3×100 mL) and the combinedorganic extracts were washed with H₂O (2×100 mL), saturated aqueousNaHCO₃ (caution, vigorous gas evolution), and brine. The organics werethen dried (MgSO₄), and concentrated under reduced pressure. Flashchromatography of the residue, (SiO₂, 100% CH₂Cl₂), gave the4-(1,1,1,3,3,3-hexafluoropropan-2-ol-2-yl)benzenesulfonyl chloride(11.42 g, 57%). ¹H NMR (CDCl₃) δ 8.17 (d, J=8.8 Hz, 2H), 8.04 (d, J=8.8Hz, 2H), 3.90 (s, 1H), MS 341.2 (M−H).

b) To a solution of 2-hydroxyethylpiperidine (300 mg, 2.32 mmol, 13.3equiv) in 5 mL CH₂Cl₂ was added 60 mg of4-(1,1,1,3,3,3-hexafluoropropan-2-ol-2-yl)benzenesulfonyl chloride(0.175 mmol, 1.0 equiv, prepared in step a). After stirring for 15 h thereaction mixture was diluted with saturated NaHCO₃ and the resultingsolution was poured into a 3M Empore 4415(SD) C18-SD octadecylhydrophobic cartridge. The organics which passed through the cartridgewere then concentrated under reduced pressure. Purification by flashchromatography (SiO₂, 1.0% MeOH/CH₂Cl₂) gave the product as a whitesolid. ¹H NMR (DMSO, 400 MHz) δ 9.07 (s, 1H), 7.99 (d, J=8.2 Hz, 2H),7.92 (d, J=8.2 Hz, 2H), 4.42 (t, J=4.6 Hz, 1H), 4.10 (m, 1H), 3.65 (m,1H), 3.35 (m, 2H), 3.00 (t, J=13.4 Hz, 1H), 1.64 (m, 2H), 1.42 (m, 4H),1.20 (m, 1H), 1.10 (m, 1H).

BIOLOGICAL EXAMPLES Procedures Useful for the Biological Evaluation ofthe Aryl Sulfonamide Compounds

In addition to the extensive literature disclosing the role of HSDs invarious diseases and disorders, we have provided assays useful fortesting the Aryl Sulfonamide Compounds of the present invention.

Assays Example 1 In Vitro 11β-HSD1 (Hydroxysteroid Dehydrogenase 1)Activity Inhibitory Action

The 11β-HSD1 inhibitory activity was examined by quantitativedetermination by an SPA (scintillation proximity assay) system of thesuppressive action on the conversion from cortisone to cortisol usinghuman 11β-HSD1 (hereinafter recombinant 11β-HSD1) expressed using abaculo-virus system as an enzyme source. For the reaction, a reagent wasadded to a 96 well plate (96 well Opti-Plates™-96 (Packard)) to thefollowing final concentration and a volume of 100 μl was reacted at roomtemperature for 90 min. The reaction solution used was 0.1 μg/mlrecombinant 11β-HSD1, 500 μM NADPH, 16 nM ³H cortisone (AmershamBiosciences, 1.78 Tbq/mol) dissolved in 0.1% BSA (Sigma)-containing PBSand the test drug was 2 μl of a compound solution (dissolved in DMSO).After 90 min, the reaction was stopped by adding PBS (40 μl, containing0.1% BSA (Sigma)) containing 0.08 μg of anti-cortisol mouse monoclonalantibody (East Coast Biologics), 365 μg SPA PVT mouse antibody-bindingbeads (Amersham Biosciences) and 175 μM carbenoxolone (Sigma) to thereaction solution. After the completion of the reaction, the plate wasincubated overnight at room temperature and the radioactivity wasmeasured by Topcount (Packard). For control, the value (0% inhibition)of the well containing 2 μl of DMSO instead of the test drug was used,and for positive control, the value (100% inhibition) of the wellcontaining carbenoxolone instead of the test drug at the finalconcentration of 50 μM was used. The inhibition (%) of the test drug wascalculated by ((value of control−value of test drug)/(value ofcontrol−value of positive control))×100 (%). The IC₅₀ value was analyzedusing a computer-based curve fitting software.

This example provides assays that are useful in evaluating and selectinga compound that modulates 11β-HSD1.

Example 2 Biochemical 11β-HSD1 Assay by SPA

Recombinant human, mouse and rat 11β-HSD1 were expressed in baculovirusexpression system, isolated by affinity purification and used as theenzyme sources for cortisone to cortisol conversion in vitro.³H-Cortisone (Amersham Bioscience, 1.78 Tbq/mol. 49 Ci/mmol) was used asthe substrate, and a monoclonal anti-cortisol antibody and thescintillation proximity assay (SPA) system were used to detect theproduct of the 11β-HSD1-catalyzed reaction, ³H-cortisol. Reactions tookplace at room temperature for 90 min. in 96-well Opti-Plates™-96(Packard) in 100 μL volume with 2 μL test compounds or control in DMSO,0.1 μg/mL 11β-HSD1 protein, 500 μM NADPH and 16 nM radioactivecortisone, in PBS buffer supplemented with 0.1% BSA (Sigma). Reactionwas stopped with the addition of 40 μL buffer containing 0.08 μganti-cortisol monoclonal antibody (East Coast Biologics), 365 μg SPA PVTantibody-binding beads (Amersham Biosciences) and 175 μM carbenoxolone(Sigma).

Plates were incubated at room temperature overnight before being read ona Topcount (Packard). The point of 50% inhibition of 11β-HSD1 enzymeactivity (IC₅₀) was determined by computer-based curve fitting.

Example 3 Cell-Based 11β-HSD1 Assay by SPA

This cell-based assay measures the conversion of ³H-cortisone to³H-cortisol in a HEK-293 cell line stably overexpressing humanrecombinant 11β-HSD1. HEK-293 cells were grown in DMEM/F12 supplementedwith 10% fetal bovine serum, and plated onto poly-D-lysine-coated96-well assay plates (Costar 3903), 100,000 cells per well in 50 μLassay media (phenol free DMEM/F12 (Invitrogen)+0.2% BSA+1%antibiotic-antimycotic solutions). The solution was incubated at 37° C.for 24 h, and the reaction was initiated by the addition of 25 μL ofassay media containing compounds of desired concentration and 25 μL ofassay media containing 40 nM of ³H-cortisone to each well. The reactionmixture was incubated at 37° C. for 90 min. and the reaction terminatedby the addition of 25 μL of assay media containing 0.2 μg ofanti-cortisol monoclonal antibody (East Coast Biologics), 500 μg SPA PVTantibody-binding beads (Amersham Biosciences) and 500 μM carbenoxolone(Sigma).

Plates were incubated at room temperature for at least 2 h before beingread on Topcount (Packard). The point of 50% inhibition of 11β-HSD1enzyme activity (IC₅₀) was determined by computer-based curve fitting.

Using the assays above, the Aryl Sulfonamide Compounds prepared in theExamples above exhibited IC₅₀ values of from 200 nM to less than 1 nM.

1. A compound having the formula:

or pharmaceutically acceptable salts or stereoisomers thereof, wherein:R¹ is a member selected from the group consisting of —OH, (C₁-C₈)alkyland (C₁-C₈)haloalkyl; R² and R³ are members independently selected fromthe group consisting of halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and(C₃-C₈)cycloalkyl; N^(cyc) is a nitrogen heterocycle having a formulaselected from the group consisting of formula (a), formula (c) andformula (d):

wherein: R^(2a), R^(2a′) and R^(5a) are each H; R^(3a) and R^(4a) areeach members independently selected from the group consisting of H,halogen, —CN, —NO₂, unsubstituted (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—C(O)N(R′)₂, —OR″, —OC(O)R′, —NR′C(O)OR″, —S(O)R″, —SO₂R″, —SO₂N(R′)₂,—N(R′)₂, and —NR′C(O)R′; and optionally two adjacent R^(3a), R^(4a) andR^(5a) members are combined to form a benzene or pyridine ring, fused tothe remainder of N^(cyc); and within formula (a), at least one ofR^(2a), R^(2a′), R^(3a), R^(4a) and R^(5a) is other than H; any fusedbenzene or pyridine ring portion of N^(cyc) is optionally substitutedwith from one to four members selected from the group consisting of H,halogen, —CN, —NO₂, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R′, —C(O)OR′,—NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″,—SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′; each occurrence of R′ isindependently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or two R′ groups, whenattached to the same nitrogen atom, can be combined with the nitrogenatom to which they are attached to form a heterocycle or heteroarylgroup; each occurrence of R″ is independently (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₄)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl or aryl(C₁-C₆)alkyl.
 2. A compound of claim 1,wherein one of R^(3a) and R^(4a) is a member selected from the groupconsisting of (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₄)heterocycloalkyl,heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl.3. A compound of claim 1, wherein R^(4a) and R^(5a) are combined to forma fused benzene ring.
 4. A compound of claim 1, wherein R¹, R² and R³are each independently selected from the group consisting of —OH,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkyl, (C₂-C₄)hydroxyalkyl and (C₃-C₅)cycloalkyl.
 5. Acompound of claim 4, wherein R¹, R² and R³ are each independentlyselected from the group consisting of —OH, (C₁-C₄)alkyl and(C₁-C₄)haloalkyl.
 6. A compound of claim 5, wherein R¹ is —OH, R² is—CH₃ and R³ is CF₃.
 7. A compound of claim 5, wherein each of R¹, R² andR³ is —CH₃.
 8. A compound of claim 5, wherein R¹ is —OH, and R² and R³are each CF₃.
 9. A pharmaceutical composition comprising the compound ofclaim 1, and a pharmaceutically acceptable carrier.
 10. A pharmaceuticalcomposition comprising the compound of claim 1, and an additionaltherapeutic agent selected from the group consisting of insulin, insulinmimetics, insulin secretogues, sulfonylureas, biguanides, α-glucosidaseinhibitors, thiazolidinone compounds, prandial glucose regulators,glucagon receptor antagonists, β3 adrenergic receptor agonists, leptinor derivatives thereof, neuropeptide Y antagonists, mazindol,cholesterol lowering agents, bile acid sequestrants, vitamin B₃, vitaminB₆, vitamin B₁₂, fibric acid derivatives, probucol, nitroglycerin,inhibitors of cholesterol absorption, HMG-CoA synthase inhibitors,squalene epoxidase inhibitors, squalene synthetase inhibitors,thrombolytic agents, heparin derivatives, hirudin derivatives, warfarinderivatives, β-blockers, β adrenergic agonists, angiotensin IIantagonists, ACE inhibitors and vasodilators, PPAR agonists, DPantagonists, petrolatum, lanolin, keratolytic agents, vitamin D₃derivatives, anthralin, etretinate, isotretinoin, cholinergic agonists,cholinesterase inhibitors, carbonic anhydrase inhibitors, non-selectiveadrenergic agonists, α₂-selective adrenergic agonists, prostaglandinanalogs, osmotic diuretics, corticosteroids, corticosteroid analogs,immunosuppressants, non-steroidal antiinflammatory agents (NSAIDs),cyclooxygenase-2 (COX-2) inhibitors, inhibitors of phosphodiesterasetype IV (PDE-IV), opioid analgesics, hepatoprotective agents, and5-aminosalicylic acid.
 11. A compound selected from the group consistingof: 5-chloro-1-(4-tert-butylphenylsulfonyl)-2,3-dihydroindole,3-(R)-1-(4-tert-butylphenylsulfonyl)-3-imidazol-1-yl)-pyrrolidine,3-(R)-1-(4-tert-butylphenylsulfonyl)-3-methoxypyrrolidine, and3-(R)-3-(piperidin-1-yl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-phenylsulfonyl)-pyrrolidine.